CN109180579A - A kind of high-efficient synthesis method of 4- iodine isoquinolines - Google Patents

A kind of high-efficient synthesis method of 4- iodine isoquinolines Download PDF

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CN109180579A
CN109180579A CN201811274357.3A CN201811274357A CN109180579A CN 109180579 A CN109180579 A CN 109180579A CN 201811274357 A CN201811274357 A CN 201811274357A CN 109180579 A CN109180579 A CN 109180579A
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iodine
isoquinolines
prepares
oac
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王元桦
方再香
王毅
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Sichuan University
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms

Abstract

The present invention relates to a kind of high-efficiency synthesis methods of 4- iodine isoquinolines, the following steps are included: under the conditions of existing for the catalyst and oxidant, the isoquinolin salt being easy to get under methanol solvate, by with the oxygen collective effect in air, one-step method obtains 4- iodine isoquinolines.This method yield is high, synthetic route is short, mild condition, easy to operate, has a good application prospect.

Description

A kind of high-efficient synthesis method of 4- iodine isoquinolines
Technical field
The isoquinolin salt being easy to get the present invention relates to a kind of lower footwork catalysis of air conditions efficiently prepares 4- iodine isoquinolines Method.
Background technique
Isoquinolines are a kind of important nitrogen-containing heterocycle compounds, natural have bioactive compound and medicine some Generally existing this kind of structural unit in object molecule.
Since the compound comprising isoquinolines structural unit has antidepression, the important life such as antiulcer and anti-hypertension Reason activity, the synthesis of isoquinolines and the like are always the hot spot of organic synthesis and have developed many synthesis sides Method.In reported synthetic method, using readily available isoquinolin salt as raw material, a step direct oxidation prepares isoquinolines It is proved to be a kind of simple and efficient method.Traditional method for oxidation needs excessive K3Fe(CN)6As oxidant, preparation It will lead to a large amount of harmful K in the process4Fe(CN)6It generates.Other methods include the oxidation function of the isoquinolin of copper or catalysis of iodine Change.Develop a kind of organic photochemical catalyst of use in recent years and, using air as oxidant, passes through freedom under the conditions of light reaction Base process prepares isoquinolines.Isoquinolin can be also prepared using the isoquinolin salt oxidation that Cabbeen is catalyzed as organic catalyst Ketone derivatives.
In the research and development of drug and drug candidate molecule, it is highly desirable to which exploitation can effectively construct the weight of pharmacophore Synthesize segment.It, then can be with rapid build drug molecule and drug molecule using isoquinolinone compound as drug molecule building block Candidate.(hetero atom) aryl iodide is widely used in the general synthon of the cross-coupling reaction of efficient metal catalysis, with Aryl bromide is compared with aryl chloride, and weaker carbon-iodine bond shows higher reactivity, promotes oxidative addition. Therefore, the functionalized isoquinolinone derivatives of iodine by be drug molecule research in ideal synthon.One typical example is 4- iodine isoquinolines are applied in a series of synthesis of CRTH2 antagonists as crucial synthetic intermediate.
The method of synthesis 4- iodine isoquinolines mainly passes through the progress of two steps at present: 1) using 1- isoquinolinol as raw material, carbon Sour caesium makees alkali, the corresponding isoquinolines of addition iodo compound synthesis under n,N-Dimethylformamide solvent, 2) in trifluoro methylsulphur Under sour silver catalysis, isoquinolines occur electrophilic substitution reaction with elemental iodine and synthesize 4- iodine isoquinolines.Bis can also be used (pyridine)iodonium.BF4Or Dipyridinium-1-yliodate is sent out under the conditions of tetrahydrofuran with isoquinolines Raw reaction.This synthetic method route is long, complicated for operation, and with duration, and yield is low.Here, we have invented a kind of one-step method by The method that the isoquinolin salt being easy to get efficiently synthesizes 4- iodine isoquinolines.Reaction uses Rh2(esp)2As catalyst, acetoxyl group Oxygen in benzo iodine ketone (IBA-OAc) and air is as oxidant.
Summary of the invention
The purpose of the present invention is intended to provide a kind of method that the isoquinolin salt that catalysis oxidation is easy to get prepares 4- iodine isoquinolines, Method of the invention is through one-step synthesis, and efficiently, the reaction time is short, and reaction condition is mild for reaction, and product conversion is high, and selectivity is strong.
The present invention provides a kind of 4- iodine compound of isobioquin group, structure is as follows:
Wherein, R1Substituent group is located at each position of phenyl ring, be it is monosubstituted, be selected from-H, halogen, aryl, ester group, AcNH-, first Base, methoxyl group, cyclopropyl.
R2Substituent group and R1Substituent group is different, is selected from C1-C7Alkyl, isopropyl, isobutyl group, allyl, CF3CH2CH2-、 ClCH2CH2-、Ph-(CH2)n-、Ar-(CH2)n-.N is independent the integer of 1-4.
Halogen is selected from one of F, Cl, Br, I.
The aryl includes but is not limited to phenyl, and the substituent group on aromatic ring is located at each position of phenyl ring, be it is monosubstituted, take Dai Jiwei halogen, methyl, methoxyl group, ester group, trifluoromethyl.
The technical solution of the present invention is as follows: using two rhodium complex Rh using the isoquinolin salt being easy to get as raw material2(esp)2To urge Agent, IBA-OAc are oxidant, and catalysis oxidation isoquinolin salt prepares 4- iodine isoquinolines.
The molar ratio of the 2- isopropyl quinoline -2- iodide and catalyst is 1000:1-100:1, preferably 1000:5.
The reaction atmosphere is a standard atmospheric pressure.
The reaction temperature is 0 DEG C -60 DEG C, preferably 50 DEG C；Reaction time is 2h-24h, preferably 5h.
Organic solvent is methanol/water=3/1, ethyl acetate/water=3/1, dimethyl carbonate/water=3/ to the present invention in the reaction 1,1,2- dichloroethanes/water=3/1, tetrahydrofuran/water=3/1, glycol dimethyl ether/water=3/1, methanol, ethyl alcohol, hexafluoro isopropyl Alcohol, preferably methanol.
Catalyst of the invention is preferably two rhodium catalyst Rh of carboxylic acid type2(esp)2。
Oxidant IBA-OAc, IBA-OH, PhI (OAc) of the invention2, preferably IBA-OAc.
The present invention separates catalyst and product by column chromatography after the completion of reaction.
The present invention is a kind of method that isoquinolin salt prepares 4- iodine isoquinolines, and preferred technical solution is as follows.
Using isoquinolin salt as raw material, under the conditions of methanol as solvent, two rhodium complex Rh are used2(esp)2For catalyst, IBA- OAc is oxidant, and catalysis oxidation prepares 4- iodine isoquinolines under atmospheric atmosphere；Wherein isoquinolin salt and Rh2(esp)2Mole Than being 1:2 for 1000:5, isoquinolin salt and IBA-OAc molar ratio, reaction temperature is 50 DEG C, reaction time 4h.
The present invention is a kind of method that isoquinolin salt prepares 4- iodine isoquinolines, and reaction equation is as follows:
Compared with tradition prepares the method for the iodo- isoquinolines of 4-, the invention has the characteristics that: 1, synthetic route is simple, a step Method realizes conversion, reduces the consumption of the energy；2, reaction condition is mild, and the reaction time is shorter, and a gram scale grade yield can reach 86%；3, environmental-friendly, the Atom economy of height, catalyst amount is low.
Specific embodiment
In order to better explain the present invention, it is further elaborated by following embodiment, but the contents of the present invention are not It is limited only to following embodiment.
Embodiment 1.
By 143mg (0.53mmol) 2- methylisoquinolinium salt compounded of iodine, 4mg(0.0053mmol) Rh2(esp)2 ,323mg (1.06mmol) is added in 25ml reaction tube, and 50o4h is stirred under C.End of reaction is added appropriate DCM, uses saturated sodium bicarbonate It washs (2X20mL), saturated sodium-chloride removes water (2X20mL), and anhydrous sodium sulfate is dry, and revolving removes solvent.Column chromatographic purifying, yield It is 85%.
Embodiment 2-10.
Similar to embodiment 1, change solvent, reacts 50o4h is reacted under C, result is as shown in Table 1.
The influence Bifunctionalized to 2- methylisoquinolinium -2- iodide of one different solvents of table.
Embodiment Organic solvent Yield/%
2 Methanol: water=3:1 52
3 1,2- dichloroethanes: water=3:1 46
4 Ethyl acetate: water=3:1 30
5 Dimethyl carbonate: water=3:1 48
6 Tetrahydrofuran: water=3:1 26
7 Glycol dimethyl ether: water=3:1 15
8 Methanol 85
9 Ethyl alcohol 72
10 Hexafluoroisopropanol trace
Embodiment 11-12.
Similar to embodiment 1, change temperature, result is as shown in Table 2.
Embodiment React temperature/oC Yield/%
11 25 61
12 40 82
The influence Bifunctionalized to 2- methylisoquinolinium -2- iodide of two different temperatures of table.
Embodiment 13-16.
Similar to embodiment 1, change the amount and other high iodine reagents of IBA-OAc, reacts 50o4h is reacted under C, is tied Fruit is as shown in Table 3.
The different amounts of IBA-OAc of table three and other high iodine reagents are Bifunctionalized to 2- methylisoquinolinium -2- iodide It influences.
Embodiment Xeq IBA-OAc Yield/%
13 1.5 49
14 2.5 82
15 2(PhI(OAc)2) 8
16 2(IBA-OH) 73
Embodiment 17-26.
Similar to embodiment 1, the amount and other catalyst of catalyst are reduced, is reacted 50o4h, result are reacted under C As shown in Table 4.
Embodiment Cat Yield/%
17 5%Cu(Acac)2 49
18 5%Co(OAc)2 13
19 1%Rh(Cp*)Cl complex
20 1%Rh2(OAc)4 14
21 1%Rh2(OPiv)4 86
22 0.5%Rh2(esp)2 86
23 0.5%Rh2(OPiv)4 82
24 0.3%Rh2(esp)2 78
25 0.3%Rh2(OPiv)4 51
26 none complex
Four difference Rh of table2(esp)2Amount and other catalyst shadow Bifunctionalized to 2- methylisoquinolinium -2- iodide It rings.
Embodiment 27.
Gram scale grade experiment: by 1g (3.34mmol) 2- isopropyl quinoline salt compounded of iodine, 13mg(0.0167mmol) Rh2 (esp)2, 2.047g(6.68mmol) and IBA-OAc is added in 50ml round-bottomed flask, it is added methanol 12mL, 50oIt is stirred under C 10h.Appropriate DCM is added in end of reaction, is washed (2X20mL) with saturated sodium bicarbonate, and saturated sodium-chloride removes water (2X20mL), nothing Aqueous sodium persulfate is dry, and revolving removes solvent.Column chromatographic purifying (n-hexane/EtOAc=20/1) obtains yellow liquid, and yield is 86%。1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.0 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 5.39 – 5.28 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H).13C NMR (100 MHz, CDCl3) δ 161.2, 136.7, 133.6, 133.2, 130.3, 128.5, 127.8, 126.8, 72.1, 46.5, 22.0.HRMS (ESI+) m/z calcd for C12H12INO 314.0036([M+H]+), found 314.0003.
The synthesis of part of compounds of the present invention, by taking compound 1a as an example.
Embodiment 28.
The synthesis of the iodo- 2- methylisoquinolinium ketone (1a) of 4-:
By 214mg (0.8mmol) 2- methylisoquinolinium salt compounded of iodine, 3mg(0.004mmol) Rh2(esp)2 ,485mg (1.6mmol) is added in 25ml reaction tube, and 50o4h is stirred under C.End of reaction is added appropriate DCM, uses saturated sodium bicarbonate It washs (2X20mL), saturated sodium-chloride removes water (2X20mL), and anhydrous sodium sulfate is dry, and revolving removes solvent.Column chromatographic purifying (n- Hexane/EtOAc=3/1) obtain 258mg white solid, yield 86%.1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.7 Hz, 1H), 7.72 (m, 1H), 7.66 (d, J = 7.0 Hz, 1H), 7.56 – 7.50 (m, 1H),7.53 (s, 1H), 3.60 (s, 3H).13C NMR (100 MHz, CDCl3) δ 162.1, 138.8, 137.3, 133.2, 130.5, 128.2, 127.9, 126.6. 71.5, 37.0.HRMS (ESI+) m/z calcd for C10H8INO 285.9723 ([M+H]+), found 285.9724.
Embodiment 29.
The synthesis of the iodo- 2,6- dimethylisoquinoline ketone (1b) of 4-:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=3/1) obtains 244 mg yellow solids.Yield is 77%.1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 3.58 (s, 3H), 2.53 (s, 3H).13C NMR (100 MHz, CDCl3) δ 162.1, 144.0, 138.8, 137.3, 130.3, 129.5, 128.3, 124.4, 71.5, 36.9, 22.1.HRMS (ESI+) m/z calcd for C11H10INO 299.9880 ([M+H]+), found 299.9856.
Embodiment 30.
The synthesis of the iodo- 2- methyl-isoquinolin ketone of 6- cyclopropyl -4-:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=10/1) obtains 175 mg yellow solids, yield 68%.1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.14 (dd, J = 8.3, 1.4 Hz, 1H), 3.57 (s, 3H), 2.11 - 2.02 (m, 1H), 1.15 - 1.08 (m, 2H), 0.89 - 0.83 (m, 2H).13C NMR (100 MHz, CDCl3) δ 162.0, 150.4, 138.9, 137.2, 128.3, 127.1, 125.3, 124.2, 71.6, 36.8, 16.1, 10.6 .HRMS (ESI+) m/z calcd for C13H12INO 326.0036 ([M+H]+), found 326.0036.
Embodiment 31.
The synthesis of the iodo- 2- methyl -6- methyl formate isoquinolines of 4-:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=5/1) obtains 133 mg yellow solids, yield 98%.1H NMR (400 MHz, DMSO) δ 8.32 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 1.3 Hz, 1H), 8.11 (s, 1H), 8.03 (dd, J = 8.3, 1.5 Hz, 1H), 3.94 (s, 3H), 3.52 (s, 3H).13C NMR (100 MHz, DMSO) δ 165.4, 160.3, 140.9, 137.0, 133.4, 131.0, 128.4,128.4, 127.0, 70.2, 52.8, 36.3. HRMS (ESI+) m/z calcd for C12H10INO3 343.9778([M+H]+), found 343.9778.
Embodiment 32.
The synthesis of 6- chlorine-4-iodine -2- methylisoquinolinium ketone:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=5/1) obtains 240mg white solid, yield 94%.1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.55 (s, 1H), 7.45 (dd, J = 8.6, 1.9 Hz, 1H), 3.59 (s, 3H).13C NMR (100 MHz, CDCl3) δ 161.4 140.1, 138.8, 130.1, 130.0, 128.4, 124.9, 69.5, 37.0.HRMS (ESI +) m/z calcd for C10H7ClINO 319.9334 ([M+H]+), found 319.9331.
Embodiment 33.
The synthesis of the iodo- 2- methylisoquinolinium ketone of 6- phenyl -4-:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=10/1) obtains 234mg yellow solid, yield 82%.1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 1.8 Hz, 1H), 7.96 (dd, J = 8.4, 1.9 Hz, 1H), 7.73 (dd, J = 4.8, 3.6 Hz, 2H), 7.71 (s, 1H), 7.53 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 3.62 (s, 3H).13C NMR (100 MHz, CDCl3) δ 162.2, 140.7, 139.6, 138.6, 136.3, 132.0, 131.1, 129.1, 128.1, 127.4, 126.8, 126.1, 71.1, 37.0.HRMS (ESI+) m/z calcd for C16H12INO 383.9856 ([M+Na]+), found 383.9842.
Embodiment 34.
The iodo- 2- methyl -6-((4- trifluoromethyl of 4-) phenyl) isoquinolines synthesis:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=5/1) obtains 295mg yellow solid, yield 87%.1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.3 Hz, 1H), 7.84 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 9.3 Hz, 1H), 7.59 (s, 1H), 3.63 (s, 3H).13C NMR (100 MHz, CDCl3) δ 161.8, 144.4, 143.4, 139.5, 137.7, 130.7, 130.4, 129.2,129.1, 128.0, 126.9, 126.1, 126.1, 126.1, 126.0, 126.0,125.6, 122.9 , 71.3, 37.0.HRMS (ESI+) m/z calcd for C17H11F3INO 429.9910 ([M+H]+), found 429.9914.
Embodiment 35.
The synthesis of the iodo- isoquinolines of 2- ethyl -4-:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=3/1) obtains 220mg yellow solid, yield 93%.1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 8.0, 0.7 Hz, 1H), 7.74 – 7.69 (m, 1H), 7.69-7.64 (m, 1H), 7.56-7.50 (m, 1H), 7.53 (s, 1H), 4.05 (Hz of q, J=7.2, 2H), 1.39 (t, J = 7.2 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 161.4, 137.7, 137.2, 133.2, 130.5, 128.3, 127.9, 126.9, 71.8, 44.5, 14.8. HRMS (ESI+) m/z calcd for C11H10INO 299.9880 ([M+H]+), found 299.9863.
Embodiment 36.
The synthesis of the iodo- isoquinolines of 2- propyl -4-:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=10/1) obtains 232mg yellow solid, yield 94%.1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 7.73 – 7.67 (m, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.50 (s, 1H), 3.97 – 3.91 (m, 2H), 1.86 - 1.75 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 161.6, 138.1, 137.2, 133.2, 130.4, 128.4, 127.9, 126.8, 71.5, 51.0, 22.8, 11.3.HRMS (ESI+) m/z calcd for C8H8N4O 314.0036 ([M+H]+), found 314.0035.
Embodiment 37.
The synthesis of the iodo- 2- isobutyl group isoquinolines of 4-:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=20/1) obtains 225mg yellow liquid, yield 87%.1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.48 (s, 1H), 3.80 (d, J = 7.4 Hz, 2H), 2.25 – 2.14 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H).13C NMR (100 MHz, CDCl3) δ 161.8, 138.6, 137.2, 133.2, 130.4, 128.4, 127.8, 126.8, 71.3, 56.6, 28.5, 20.1.HRMS (ESI+) m/z calcd for C13H14INO 328.0193 ([M+H]+), found 328.0195.
Embodiment 38.
The iodo- 2-(3,3,3- trifluoro propyl of 4-) isoquinolines synthesis:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=10/1) obtains 273mg yellow solid, yield 94%.1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.0 Hz, 1H), 7.78 – 7.72 (m, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.50 (s, 1H), 4.19 (t, J = 7.0 Hz, 2H), 2.67 (qt, J = 10.6, 7.0 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 161.6 , 137.7, 137.3, 133.7, 130.7, 128.3, 128.2, 127.4, 126.4, 124.6, 72.3, 43.9, 33.4, 33.1, 32.8, 32.5.HRMS (ESI+) m/z calcd for C12H9F3INO 367.9754 ([M+H]+), found 367.9747.
Embodiment 39.
2-(4- bromobenzyl) -4- iodine isoquinolines synthesis:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=10/1) obtains 158mg yellow solid, yield 91%.1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.0 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.51 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 5.13 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 161.7, 137.4, 137.2 135.5, 133.6, 132.2, 130.7, 129.8, 128.5, 128.2, 126.7, 122.3, 72.6, 51.4.HRMS (ESI+) m/z calcd for C16H11BrINO 461.8961 ([M+H]+), found461.8960.
Embodiment 40.
The iodo- 2-(3- phenylpropyl of 4-) isoquinolines synthesis:
Operate same 1a.Column chromatographic purifying (n-hexane/EtOAc=10/1) obtains 302mg yellow solid, yield 98%.1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 8.0, 0.8 Hz, 1H), 7.75 – 7.67 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.44 (s, 1H), 7.32 – 7.27 (m, 2H), 7.23 – 7.17 (m, 3H), 4.03 – 3.97 (m, 2H), 2.72 (t, J = 7.7 Hz, 2H), 2.18 – 2.10 (m, 2H).13C NMR (100 MHz, CDCl3) δ 161.6, 140.8, 138.1, 137.2, 133.3, 130.4,128.7, 128.5, 128.3, 127.9, 126.8, 126.3, 71.7, 49.1, 32.9, 30.6.HRMS (ESI+) m/z calcd for C18H16INO 390.0349 ([M+H]+), found 390.0342.
The purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the scope of the invention.In addition, reading After technology contents of the invention, those skilled in the art be can make various modifications, alterations and/or variations to the present invention, institute Some such equivalent forms are equally fallen within the scope of the appended claims within the limits of the protection.

Claims (10)

1. a kind of method that the isoquinolin salt that the lower footwork catalysis of air conditions is easy to get efficiently prepares 4- iodine isoquinolines.
2. described it is characterized in that being made under the conditions of methanol solvate with the isoquinolin salt raw material being easy to get according to claim 1 With two rhodium complex Rh2(esp)2For catalyst, IBA-OAc is oxidant, and catalysis oxidation prepares 4- iodine isoquinolines；It is described different The molar ratio of quinolinium and catalyst is 10000:1-100:1；The molar ratio of the isoquinolin salt and oxidant is 1:1-1:10； The reaction temperature is 0 DEG C -60 DEG C, reaction time 2h-12h.
3.
The R according to claim 11Substituent group is located at each position of phenyl ring, be it is monosubstituted, selected from-H, halogen, aryl, Ester group, AcNH-, methyl, methoxyl group, cyclopropyl.
4. the R according to claim 12Substituent group and R1Substituent group is different, is selected from C1-C7Alkyl, isopropyl, isobutyl group, Allyl, CF3CH2CH2-、ClCH2CH2-、Ph-(CH2)n-、Ar-(CH2)n-。
5. the n is independent the integer of 1-4 according to claim 1.
6. the aryl includes but is not limited to phenyl according to claim 1, the substituent group on aromatic ring is located at each of phenyl ring Position, be it is monosubstituted, substituent group be halogen, methyl, methoxyl group, ester group, trifluoromethyl.
7. halogen is selected from one of F, Cl, Br, I according to claim 1.
8. the method that isoquinolin salt prepares 4- iodine isoquinolines according to claim 1, which is characterized in that the oxidant is Acetoxyl group benzo iodine ketone (IBA-OAc).
9. the method that isoquinolin salt prepares 4- iodine isoquinolines according to claim 1, which is characterized in that used catalysis Agent is Rh2(esp)2。
10. the method that isoquinolin salt prepares 4- iodine isoquinolines according to claim 1, which is characterized in that different with what is be easy to get Quinolinium is raw material, under the conditions of methanol solvate, uses two rhodium complex Rh2(esp)2For catalyst, IBA-OAc is oxidant, Catalysis oxidation prepares 4- iodine isoquinolines under air conditions；The isoquinolin salt and Rh2(esp)2Molar ratio be 1000:5；Institute The molar ratio for stating isoquinolin salt and IBA-OAc is 1:2；The reaction temperature is 50 DEG C, reaction time 4h.
CN201811274357.3A 2018-10-29 2018-10-29 A kind of high-efficient synthesis method of 4- iodine isoquinolines Pending CN109180579A (en)

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