CN106831542B - A kind of synthetic method of ring-type enamine -3- formic ether compounds - Google Patents
A kind of synthetic method of ring-type enamine -3- formic ether compounds 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 methods of cyclic annular enamine -3- formic ether compounds, belong to technical field of organic synthesis.Technical solution of the present invention main points are as follows:；
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
At method.
Background technique
Cyclic annular enamine -3- formic ether compounds not only have significant bioactivity, but also 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
Directly by the concern of chemists.Currently, such compound is mainly obtained by following approach: 1) N- benzyl-γ-chloro propylamine
With the condensation reaction of conjugation acetylenic acid ester；2) [3+3] cyclization of triphenyl phosphine catalyst aziridine and connection olefin(e) acid ester；3) primary
Aminated compounds, beta-dicarbonyl compound, alpha, beta-unsaturated aldehyde and one pot of four component reaction of alcohol etc..Although these methods can be with
Effective synthesis of cyclic enamine -3- formic ether compounds, but there are still some urgent problems, such as: the original of reaction
Subeconomy is low, severe reaction conditions and raw material are difficult to obtain, these shortcomings but also the above method practicability
It is very limited.In view of this, further studying and developing from the raw material being easy to get, synthesize under mild reaction conditions
Simple and direct, the efficient new method of cyclic annular enamine -3- formic ether compounds has important theory significance and application value.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of synthetic method of cyclic annular enamine -3- formic ether compounds,
This method be using azacycloalkyl hydro carbons compound, carbon monoxide and alcohol compound as raw material, it is direct by one pot of tandem reaction
Cyclic annular enamine -3- formic ether compounds, easy to operate, mild condition are obtained, wide application range of substrates is suitable for industrial metaplasia
It produces.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of ring-type enamine -3- formate ester chemical combination
The synthetic method of object, it is characterised in that: azacycloalkyl hydro carbons compound 1 and alcohol compound 2 are dissolved in solvent, are then added
Catalyst, oxidant and additive, in CO atmosphere or CO and O2Mixed atmosphere in, cyclic annular alkene is made in 60-100 DEG C of reaction
Amine -3- formic ether compounds 3, the reaction equation in the synthetic method are as follows:
Wherein R1For benzyl, substituted benzyl, phenethyl, C1-10Linear or branched alkyl group, cyclopenta, phenyl or substituted-phenyl,
Substituent group on the substituted benzyl phenyl ring is cyano, fluorine, chlorine, bromine, methyl or methoxy, and the substituent group on substituted-phenyl phenyl ring is
One or more fluorine, chlorine, bromine, methyl or methoxy, R2For hydrogen or methyl, R3For benzyl or C1-5Linear or branched alkyl group, n 1
Or 2, catalyst is palladium acetate, palladium chloride or tris(dibenzylideneacetone) dipalladium, and oxidant is copper acetate, copper bromide or chlorination
Copper, additive are potassium iodide, potassium bromide, potassium chloride or elemental iodine, and solvent is toluene, dichloroethanes, Isosorbide-5-Nitrae-dioxane or second
Nitrile.
It further limits, azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst, oxidant and the addition
The ratio between amount for the substance that feeds intake of agent is 1:5-10:0.05-0.1:0.2-1:1.
The synthetic method of a kind of cyclic annular 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, and catalyst and oxidant is then added, CO atmosphere or CO with
O2Mixed atmosphere in, reacted in 60-100 DEG C and ring-type enamine -3- formic ether compounds 3 be made, it is anti-in the synthetic method
Answer equation are as follows:
Wherein R1For benzyl, substituted benzyl, phenethyl, C1-10Linear or branched alkyl group, cyclopenta, phenyl or substituted-phenyl,
Substituent group on the substituted benzyl phenyl ring is cyano, fluorine, chlorine, bromine, methyl or methoxy, and the substituent group on substituted-phenyl phenyl ring is
One or more fluorine, chlorine, bromine, methyl or methoxy, R2For hydrogen or methyl, R3For benzyl or C1-5Linear or branched alkyl group, n 1
Or 2, catalyst is palladium acetate, palladium chloride or tris(dibenzylideneacetone) dipalladium, and oxidant is copper acetate, copper bromide or chlorination
Copper, solvent are toluene, dichloroethanes, Isosorbide-5-Nitrae-dioxane or acetonitrile.
It further limits, the azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst and oxidant feed intake
The ratio between amount of substance is 1:5-10:0.05-0.1:0.2-1.
Compared with the prior art, the present invention has the following advantages: (1) one pot of tandem reaction is used, cumbersome centre is avoided
Body isolates and purifies process, reduces waste discharge, reduces environmental pressure；(2) raw material is readily available；(3) reaction 100 DEG C with
Lower progress, mild condition are easy to operate；(4) substrate is applied widely；(5) Atom economy reacted is high.Therefore, this hair
The bright synthesis for cyclic annular enamine -3- formic ether compounds provides a kind of economical and practical and environmentally protective new method.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
1a (0.5mmol, 88mg) and acetonitrile (CH are added in the reaction flask of 25mL3CN, 5mL), 2a is then added
(5mmol, 292 μ L), palladium chloride (PdCl2, 0.05mmol, 9mg), copper acetate (Cu (OAc)2, 0.1mmol, 18mg) and potassium iodide
(KI,0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorine
Change sodium solution quenching reaction, be extracted with ethyl acetate (10mL × 3), merges organic phase, it is dry with anhydrous sodium sulfate.Filtering, rotation
It is dry, it crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (92mg, 75%).The compound
Characterize data is as follows:1H NMR(400MHz,CDCl3) δ 1.28 (t, J=7.2Hz, 3H), 1.79-1.82 (m, 2H), 2.31 (t, J
=6.4Hz, 2H), 3.00 (t, J=6.0Hz, 2H), 4.16 (q, J=7.2Hz, 2H), 4.30 (s, 2H), 7.23 (d, J=
6.8Hz,2H),7.31-7.36(m,3H),7.56(s,1H).13C NMR(100MHz,CDCl3)δ14.7,20.0,21.3,
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
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium acetate (0.05mmol, 11mg) and copper acetate (0.5mmol, 91mg) is added.In CO
In (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, 10mL saturated sodium chloride solution quenching reaction is then added, with acetic acid second
Ester extracts (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silica gel post separation (petroleum ether/second
Acetoacetic ester=20:1) obtain yellow liquid product 3a (59mg, 48%).
Embodiment 3
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then be added 2a (5mmol, 292 μ L), tris(dibenzylideneacetone) dipalladium (0.05mmol, 46mg) and copper acetate (0.5mmol,
91mg).It in CO (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL saturated sodium chloride solution is then added and is quenched instead
It answers, is extracted with ethyl acetate (10mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silica gel post separation
(petrol ether/ethyl acetate=20:1) obtains yellow liquid product 3a (43mg, 35%).
Embodiment 4
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg) and copper bromide (0.5mmol, 111mg) is added.In CO
In (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, 10mL saturated sodium chloride solution quenching reaction is then added, with acetic acid second
Ester extracts (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silica gel post separation (petroleum ether/second
Acetoacetic ester=20:1) obtain yellow liquid product 3a (15mg, 12%).
Embodiment 5
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg) and copper chloride (0.5mmol, 67mg) is added.At CO (1atm)
In atmosphere, it is stirred to react in 80 DEG C 12 hours, 10mL saturated sodium chloride solution quenching reaction is then added, is extracted with ethyl acetate
(10mL × 3) merge organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silica gel post separation (petrol ether/ethyl acetate
=20:1) obtain yellow liquid product 3a (12mg, 10%).
Embodiment 6
By method described in embodiment 1,1a (0.5mmol, 88mg) and dichloroethanes are added in the reaction flask of 25mL
2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and iodate is then added in (5mL)
Potassium (0.5mmol, 83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorine
Change sodium solution quenching reaction, be extracted with ethyl acetate (10mL × 3), merges organic phase, it is dry with anhydrous sodium sulfate.Filtering, rotation
It is dry, it crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (71mg, 58%).
Embodiment 7
By method described in embodiment 1,1a (0.5mmol, 88mg) and Isosorbide-5-Nitrae-dioxy six are added in the reaction flask of 25mL
2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and iodine is then added in ring (5mL)
Change potassium (0.5mmol, 83mg).In CO/O2In (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, 10mL saturation is then added
Sodium chloride solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering,
It is spin-dried for, crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtain yellow liquid product 3a (80mg, 65%).
Embodiment 8
By method described in embodiment 1,1a (0.5mmol, 88mg) and toluene (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (49mg, 40%).
Embodiment 9
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.5mmol, 91mg) and potassium bromide is added
(0.5mmol,59mg).In CO (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, it is molten that 10mL saturated sodium-chloride is then added
Liquid quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silicon
Rubber column gel column separates (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (76mg, 62%).
Embodiment 10
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.5mmol, 91mg) and elemental iodine is added
(0.5mmol,127mg).In CO (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, 10mL saturated sodium-chloride is then added
Solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, mistake
Silica gel post separation (petrol ether/ethyl acetate=20:1) obtains yellow liquid product 3a (86mg, 70%).
Embodiment 11
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.5mmol, 91mg) and potassium chloride is added
(0.5mmol,37mg).In CO (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, it is molten that 10mL saturated sodium-chloride is then added
Liquid quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silicon
Rubber column gel column separates (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (65mg, 53%).
Embodiment 12
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.025mmol, 5mg), copper acetate (0.5mmol, 91mg) and potassium iodide is added
(0.5mmol,83mg).In CO (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, it is molten that 10mL saturated sodium-chloride is then added
Liquid quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silicon
Rubber column gel column separates (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (49mg, 40%).
Embodiment 13
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.25mmol, 46mg) and potassium iodide is added
(0.5mmol,83mg).In CO (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, it is molten that 10mL saturated sodium-chloride is then added
Liquid quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silicon
Rubber column gel column separates (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (43mg, 35%).
Embodiment 14
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (2.5mmol, 146 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.5mmol, 91mg) and potassium iodide is added
(0.5mmol,83mg).In CO (1atm) atmosphere, it is stirred to react in 80 DEG C 12 hours, it is molten that 10mL saturated sodium-chloride is then added
Liquid quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for, and crosses silicon
Rubber column gel column separates (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (51mg, 42%).
Embodiment 15
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 100 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a (86mg, 70%).
Embodiment 16
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 60 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3a ((76mg, 62%).
Embodiment 17
By method described in embodiment 1,1b (0.5mmol, 95mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3b (97mg, 75%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3) δ 1.25-1.29 (m, 3H), 1.83 (t, J=5.6Hz, 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(100MHz,CDCl3)δ14.7,19.2,20.1,21.3,45.6,57.5,58.9,94.7,126.2,127.8,128.0,
130.7,134.8,136.4,146.2,168.8.HRMS calcd forC16H21NO2Na:282.1465[M+Na]+,found:
282.1462。
Embodiment 18
By method described in embodiment 1,1c (0.5mmol, 97mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3c (101mg, 77%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ 1.27-1.30 (m, 3H), 1.82 (t, J=5.6Hz, 2H), 2.31 (t, J=
6.0Hz, 2H), 3.01 (t, J=6.4Hz, 2H), 4.17 (q, J=7.2Hz, 2H), 4.29 (s, 2H), 6.92-7.02 (m, 3H),
7.32-7.34(m,1H),7.52(s,1H).13C NMR(100MHz,CDCl3)δ14.7,19.9,21.2,45.5,59.1,
59.2,95.4,114.2(d,2JC-F=21.0Hz), 114.7 (d,2JC-F=20.8Hz), 122.9,130.3 (d,3JC-F=
9.1Hz),139.9(d,4JC-F=6.2Hz), 146.0,163.1 (d,1JC-F=245.5Hz), 168.7.HRMS calcd for
C15H19FNO2:264.1394[M+H]+,found:264.1395。
Embodiment 19
By method described in embodiment 1,1d (0.5mmol, 103mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3d (117mg, 85%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ 1.28 (t, J=7.2Hz, 3H), 1.77-1.80 (m, 2H), 2.29 (t, J=
6.0Hz, 2H), 2.97 (t, J=6.0Hz, 2H), 3.82 (s, 3H), 4.16 (q, J=6.8Hz, 2H), 4.23 (s, 2H), 6.88
(d, J=8.8Hz, 2H), 7.15 (d, J=8.8Hz, 2H), 7.55 (s, 1H)13C NMR(100MHz,CDCl3)δ14.7,
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
By method described in embodiment 1,1e (0.5mmol, 105mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3e (110mg, 79%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ 1.26-1.30 (m, 3H), 1.79-1.82 (m, 2H), 2.30 (t, J=
6.4Hz, 2H), 2.97 (t, J=6.0Hz, 2H), 4.16 (q, J=7.2Hz, 2H), 4.26 (s, 2H), 7.16 (d, J=8.4Hz,
2H), 7.33 (d, J=8.0Hz, 2H), 7.52 (s, 1H)13C NMR(100MHz,CDCl3)δ14.7,20.0,21.2,45.4,
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
By method described in embodiment 1,1f (0.5mmol, 100mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3f (95mg, 70%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3)δ1.26-1.30(m,3H),1.82(s,2H),2.31(s,2H),2.99(s,
2H), 4.16 (q, J=6.8Hz, 2H), 4.35 (s, 2H), 7.34 (d, J=7.6Hz, 2H), 7.49 (s, 1H), 7.66 (d, J=
7.2Hz,2H).13C NMR(100MHz,CDCl3)δ14.7,19.9,21.2,30.9,45.8,59.2,96.3,111.7,
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
By method described in embodiment 1,1g (0.5mmol, 95mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3g (101mg, 78%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ 1.25 (t, J=7.2Hz, 3H), 1.75-1.81 (m, 2H), 2.25 (t, J=
6.4Hz, 2H), 2.83 (t, J=7.2Hz, 2H), 3.07 (t, J=5.6Hz, 2H), 3.34 (t, J=7.2Hz, 2H), 4.12 (q,
J=7.2Hz, 2H), 7.17 (d, J=8.4Hz, 2H), 7.21-7.32 (m, 4H)13C NMR(100MHz,CDCl3)δ14.7,
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
By method described in embodiment 1,1h (0.5mmol, 57mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3h (75mg, 82%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3)δ1.14-1.18(m,3H),1.24-1.29(m,3H),1.79-1.85(m,2H),
2.26-2.29 (m, 2H), 3.09 (t, J=6.0Hz, 2H), 3.15-3.21 (m, 2H), 4.11-4.17 (m, 2H), 7.38 (s,
1H).13C NMR(100MHz,CDCl3)δ13.9,14.7,20.1,21.4,29.7,45.2,50.4,58.8,93.8,145.5,
168.8.HRMS calcd for C10H18NO2:184.1332[M+H]+,found:184.1343。
Embodiment 24
By method described in embodiment 1,1i (0.5mmol, 99mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3i (112mg, 84%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ 0.88 (t, J=7.2Hz, 3H), 1.24-1.32 (m, 13H), 1.53 (t, J
=6.8Hz, 2H), 1.76-1.84 (m, 2H), 2.27 (t, J=6.0Hz, 2H), 3.08 (q, J=6.8Hz, 4H), 4.13 (q, J
=6.8Hz, 2H), 7.35 (s, 1H)13C NMR(100MHz,CDCl3)δ14.1,14.7,20.1,21.4,22.6,26.6,
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
By method described in embodiment 1,1j (0.5mmol, 77mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3j (61mg, 55%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3) δ 1.20-1.27 (m, 3H), 1.56-1.87 (m, 10H), 2.28 (t, J=
6.4Hz, 2H), 3.07 (t, J=5.6Hz, 2H), 3.59 (t, J=8.0Hz, 1H), 4.13 (q, J=7.2Hz, 2H), 7.47 (s,
1H).13C NMR(100MHz,CDCl3)δ14.8,20.6,21.6,23.9,29.9,43.4,58.8,65.8,93.6,144.8,
168.9.HRMS calcd for C13H21NO2Na:246.1465[M+Na]+,found:246.1484。
Embodiment 26
By method described in embodiment 1,1k (0.5mmol, 81mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3k (75mg, 65%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3) δ 1.29 (t, J=7.2Hz, 3H), 1.97-2.00 (m, 2H), 2.39 (t, J=
6.4Hz, 2H), 3.60 (t, J=5.6Hz, 2H), 4.19 (q, J=7.2Hz, 2H), 7.06 (t, J=7.6Hz, 3H), 7.32-
7.36(m,2H),7.89(s,1H).13C NMR(100MHz,CDCl3)δ14.6,20.6,21.5,46.1,53.4,59.4,
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
By method described in embodiment 1,1l (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3l (69mg, 56%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3)δ1.23-1.28(m,3H),1.94-2.01(m,2H),2.28(s,3H),2.41
(t, J=6.4Hz, 2H), 3.43 (t, J=5.6Hz, 2H), 4.15 (q, J=7.2Hz, 2H), 7.07 (dd, J1=7.2Hz, J2=
1.2Hz,1H),7.14-7.24(m,3H),7.47(s,1H).13C NMR(100MHz,CDCl3)δ14.6,18.2,20.5,
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
By method described in embodiment 1,1m (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3m (86mg, 70%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3)δ1.25-1.30(m,3H),1.95-1.98(m,2H),2.31(s,3H),2.38
(t, J=6.4Hz, 2H), 3.57 (t, J=5.6Hz, 2H), 4.18 (q, J=7.2Hz, 2H), 6.97 (dd, J1=6.8Hz, J2=
2.0Hz, 2H), 7.14 (d, J=8.0Hz, 2H), 7.85 (s, 1H)13C NMR(100MHz,CDCl3)δ14.7,20.5,20.6,
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
By method described in embodiment 1,1n (0.5mmol, 96mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3n (104mg, 80%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ 1.25-1.30 (m, 3H), 1.95-1.98 (m, 2H), 2.38 (t, J=
6.4Hz, 2H), 3.55 (t, J=5.6Hz, 2H), 3.80 (s, 3H), 4.18 (q, J=7.2Hz, 2H), 6.88 (dd, J1=
6.8Hz,J2=2.0Hz, 2H), 7.01 (dd, J1=6.8Hz, J2=2.4Hz, 2H), 7.78 (s, 1H)13C NMR(100MHz,
CDCl3)δ14.7,20.4,21.5,46.8,55.6,59.3,99.6,114.6,119.5,140.0,141.4,155.7,
168.7.HRMS calcd for C15H20NO3:262.1438[M+H]+,found:262.1439。
Embodiment 30
By method described in embodiment 1,1o (0.5mmol, 90mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3o (62mg, 50%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3) δ 1.25-1.30 (m, 3H), 1.96-1.99 (m, 2H), 2.38 (t, J=6.4Hz,
2H), 3.56 (t, J=5.6Hz, 2H), 4.18 (q, J=7.2Hz, 2H), 7.00-7.03 (m, 4H), 7.78 (s, 1H)13C NMR
(100MHz,CDCl3)δ14.6,20.4,21.4,46.6,59.4,101.0,115.9,116.0(d,2JC-F=21.8Hz),
119.2(d,3JC-F=8.0Hz), 140.7,142.4 (d,4JC-F=2.9Hz), 158.7 (d,1JC-F=241.5Hz),
168.5.HRMS calcd for C14H17FNO2:250.1238[M+H]+,found:250.1243。
Embodiment 31
By method described in embodiment 1,1p (0.5mmol, 102mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3p (104mg, 76%).The table of the compound
It is as follows to levy data:1H NMR(400MHz,CDCl3) δ 1.23 (t, J=7.2Hz, 3H), 1.98-2.01 (m, 2H), 2.19 (s,
6H), 2.28 (s, 1H), 2.41 (t, J=6.0Hz, 2H), 3.29 (t, J=5.6Hz, 2H), 4.12 (q, J=7.2Hz, 2H),
6.90(s,2H),7.30(s,1H).13C NMR(100MHz,CDCl3)δ14.7,17.9,20.3,20.9,21.5,47.6,
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
By method described in embodiment 1,1q (0.5mmol, 95mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3q (91mg, 70%).The characterization of the compound
Data are as follows:1H NMR(600MHz,CDCl3) δ 1.06 (d, J=6.0Hz, 3H), 1.27 (t, J=7.2Hz, 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(150MHz,CDCl3)δ14.7,16.5,17.3,
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
By method described in embodiment 1,1r (0.5mmol, 95mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3r (95mg, 73%).The characterization of the compound
Data are as follows:1H NMR(600MHz,CDCl3) δ 1.04 (d, J=6.6Hz, 3H), 1.27 (t, J=7.2Hz, 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=7.8Hz, 2H), 7.28-7.36 (m, 3H), 7.53 (s,
1H).13C NMR(150MHz,CDCl3)δ14.7,22.0,24.1,27.9,41.1,58.8,59.8,100.4,127.3,
127.7,128.8,137.2,145.6,168.6.HRMS calcd for C16H22NO2:260.1645[M+H]+,found:
260.1652。
Embodiment 34
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2b (5mmol, 202 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3s (83mg, 72%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3) δ 1.79-1.82 (m, 2H), 2.30 (t, J=6.0Hz, 2H), 3.01 (t, J=
5.6Hz,2H),3.70(s,3H),4.30(s,2H),7.22-7.37(m,5H),7.56(s,1H).13C NMR(100MHz,
CDCl3)δ20.0,21.3,45.4,50.6,59.8,94.5,127.4,127.8,128.8,137.0,146.3,169.2.HRMS
calcd for C14H18NO2:232.1332[M+H]+,found:232.1332。
Embodiment 35
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2c (5mmol, 382 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3t (78mg, 60%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3) δ 0.97 (t, J=7.2Hz, 3H) 1.65-1.71 (m, 2H), 1.81 (t, J=
6.0Hz, 2H), 2.31 (t, J=6.0Hz, 2H), 3.00 (t, J=5.6Hz, 2H), 4.07 (t, J=6.4Hz, 2H), 4.31 (s,
2H),7.22-7.38(m,5H),7.56(s,1H).13C NMR(100MHz,CDCl3)δ10.6,20.0,21.3,22.4,45.4,
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
By method described in embodiment 1,1a (0.5mmol, 88mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2d (5mmol, 519 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3u (83mg, 54%).The characterization of the compound
Data are as follows:1H NMR(600MHz,CDCl3) δ 1.80 (t, J=6.0Hz, 2H), 2.33 (t, J=6.0Hz, 2H), 3.00 (t, J
=6.0Hz, 2H), 4.28 (s, 2H), 5.16 (s, 2H), 7.20-7.39 (m, 5H), 7.59 (s, 1H)13C NMR(150MHz,
CDCl3)δ20.0,21.2,30.9,45.5,59.8,64.8,94.4,127.4,127.6,127.8,127.9,128.4,
128.8,136.9,137.7,146.6,168.4.HRMS calcd for C20H21NO2Na:330.1465[M+Na]+,found:
330.1460。
Embodiment 37
By method described in embodiment 1,1s (0.5mmol, 110mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3v (118mg, 82%).The table of the compound
It is as follows to levy data:1H NMR(600MHz,CDCl3) δ 1.02 (d, J=6.6Hz, 3H), 1.27 (t, J=7.2Hz, 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=8.4Hz, 2H), 7.13 (d, J=8.4Hz, 2H), 7.53 (s,
1H).13C NMR(150MHz,CDCl3)δ14.7,22.0,24.1,27.9,40.9,55.3,58.8,59.3,100.2,114.1,
128.7,129.0,145.5,159.2,168.7.HRMS calcd for C17H23NO3Na:312.1570[M+Na]+,found:
312.1564。
Embodiment 38
By method described in embodiment 1,1t (0.5mmol, 95mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3w (78mg, 60%).The characterization of the compound
Data are as follows:1H NMR(400MHz,CDCl3) δ 1.15 (t, J=7.2Hz, 3H), 1.84-1.85 (m, 4H), 2.21 (d, J=
3.2Hz, 3H), 2.59 (t, J=6.0Hz, 2H), 3.57 (t, J=6.0Hz, 2H), 4.04 (q, J=7.2Hz, 2H), 7.05-
7.14(m,4H),7.33(s,1H).13C NMR(150MHz,CDCl3)δ14.6,18.2,25.4,26.7,28.9,54.2,
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
By method described in embodiment 1,1u (0.5mmol, 127mg) and acetonitrile (5mL) are added in the reaction flask of 25mL,
Then 2a (5mmol, 292 μ L), palladium chloride (0.05mmol, 9mg), copper acetate (0.1mmol, 18mg) and potassium iodide is added
(0.5mmol,83mg).In CO/O2It in (1atm) atmosphere, is stirred to react in 80 DEG C 12 hours, 10mL is then added and is saturated chlorination
Sodium solution quenching reaction is extracted with ethyl acetate (10mL × 3), merges organic phase, dry with anhydrous sodium sulfate.Filtering, is spin-dried for,
It crosses silica gel post separation (petrol ether/ethyl acetate=20:1) and obtains yellow liquid product 3x (82mg, 51%).The characterization of the compound
Data are as follows:1H NMR(600MHz,CDCl3) δ 1.28 (t, J=7.2Hz, 3H), 1.82-1.89 (m, 4H), 2.62 (t, J=
6.0Hz, 2H), 3.86 (t, J=6.0Hz, 2H), 4.18 (q, J=7.2Hz, 2H), 6.92 (d, J=9.0Hz, 2H), 7.40 (d,
J=9.0Hz, 2H), 7.62 (s, 1H)13C NMR(150MHz,CDCl3)δ14.5,24.9,25.2,27.4,50.1,60.0,
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 basic principles and main features of the invention and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen 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 is then added, in CO atmosphere or CO and O2Mixing
In atmosphere, is reacted in 60-100 DEG C and ring-type enamine -3- formic ether compounds 3 are made, the reaction equation in the synthetic method
Are as follows:
Wherein R1For benzyl, substituted benzyl, phenethyl, C1-10Linear or branched alkyl group, cyclopenta, phenyl or substituted-phenyl, this takes
It is cyano, fluorine, chlorine, bromine, methyl or methoxy for the substituent group on benzyl phenyl ring, the substituent group on substituted-phenyl phenyl ring is one
Or multiple fluorine, chlorine, bromine, methyl or methoxy, R2For hydrogen or methyl, R3For benzyl or C1-5Linear or branched alkyl group, n are 1 or 2,
Catalyst is palladium acetate, palladium chloride or tris(dibenzylideneacetone) dipalladium, and oxidant is copper acetate, copper bromide or copper chloride, is added
Adding agent is potassium iodide, potassium bromide, potassium chloride or elemental iodine, and 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: described
Azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst, oxidant and additive the ratio between the amount for the substance that feeds intake 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 is then added, in CO atmosphere or CO and O2Mixed atmosphere in,
It is reacted in 60-100 DEG C and ring-type enamine -3- formic ether compounds 3 is made, the reaction equation in the synthetic method are as follows:
Wherein R1For benzyl, substituted benzyl, phenethyl, C1-10Linear or branched alkyl group, cyclopenta, phenyl or substituted-phenyl, this takes
It is cyano, fluorine, chlorine, bromine, methyl or methoxy for the substituent group on benzyl phenyl ring, the substituent group on substituted-phenyl phenyl ring is one
Or multiple fluorine, chlorine, bromine, methyl or methoxy, R2For hydrogen or methyl, R3For benzyl or C1-5Linear or branched alkyl group, n are 1 or 2,
Catalyst be palladium acetate, palladium chloride or tris(dibenzylideneacetone) dipalladium, oxidant be copper acetate, copper bromide 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: described
Azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst and oxidant the ratio between the amount for the substance that feeds intake be 1:5-10:
0.05-0.1:0.2-1。
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