CN108440530A - A kind of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton and preparation method thereof - Google Patents

A kind of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton and preparation method thereof Download PDF

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CN108440530A
CN108440530A CN201810354461.7A CN201810354461A CN108440530A CN 108440530 A CN108440530 A CN 108440530A CN 201810354461 A CN201810354461 A CN 201810354461A CN 108440530 A CN108440530 A CN 108440530A
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acid
oxoindoles
tetrahydroisoquinoline
loop coil
double loop
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王琪琳
郭娇美
卜站伟
徐括喜
常海波
杨浩
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Henan University
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Henan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention discloses a kind of tetrahydroisoquinolines and the double loop coil Oxoindoles of pyrrole skeleton and preparation method thereof, belong to technical field of organic synthesis.Isatin, tetrahydroisoquinoline and 3 alkene Oxoindoles by being added in toluene solvant by the present invention, using trifluoracetic acid as catalyst, 50o[3+2] cycloaddition reaction of three components occurs at a temperature of C to prepare double loop coil Oxoindoles.The present invention avoids separation of intermediates by the way for the treatment of different things alike, and after the reaction was complete, sterling can be taken by column chromatography or simple filtering.The present invention has many advantages, such as that reaction condition is mild, easy to operate, substrate spectrum is wide.

Description

A kind of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton and preparation method thereof
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton And preparation method thereof.
Background technology
Special representative of double loop coil Oxoindoles as Oxoindole is the important activity bone of many natural products and drug Frame has important physiological activity.As there is compound I antitumor activity, compound II to have active anticancer, compound III It is acetylcholinesterase inhibitor, compound IV has antifungal activity, and compound V is fungicide.Therefore, development is efficient closes The method of loop coil Oxoindole in pairs has highly important theory significance and realistic price.Carry out the research of this respect, not only The type of double loop coil Oxoindoles is enriched, while also providing more candidate molecules for drug screening.Since double loop coils aoxidize Indoles has highly complex and very crowded design feature, how to efficiently synthesize such compound and brings one to chemists Fixed difficulty and challenge.[3+2] cycloaddition reaction provides a very efficient method for the synthesis of double loop coil Oxoindoles And means.But 1, the 3- dipoles developed at present are mainly by amino acid and isatin in-situ preparation, since amino acid classes are limited, Greatly limit the diversity of product structure.Therefore, exploitation other types synthon is to the novel double loop coil oxygen of composite structure Change indoles tool to have very important significance.
Invention content
For problems of the prior art, a kind of structure novel tetrahydroisoquinoline of present invention offer and pyrrole skeleton pair Loop coil Oxoindole and preparation method thereof, easy to operate, reaction condition is mild, yield is up to 91%.
In order to solve the above technical problems, the present invention uses following technical scheme：
A kind of tetrahydroisoquinoline and double loop coil Oxoindoles of pyrrole skeleton, structural formula are as follows：
Wherein, R1For alkyl；R2For H, halogen atom or alkyl；R3For halogen atom；R4For Alkoxy carbonyl group or sulfonyl；R5For ester group；R6For H, halogen atom or alkyl.
The preparation method of the double loop coil Oxoindoles of tetrahydroisoquinoline and pyrrole skeleton, by various substitution isatin, four Hydrogen isoquinoline and 3- alkene Oxoindoles, in organic solvent, acid in the presence of, 25-100 DEG C reaction 24-72h, thin-layer chromatography with Track is reacted to complete, and after the reaction was complete, solvent evaporated by column chromatography or is separated by filtration purifying, obtains target product, and reaction is logical Formula is as follows：
Wherein, R1For alkyl；R2For H, halogen atom or alkyl；R3For halogen atom；R4For alkoxy carbonyl group or sulfonyl；R5For ester Base；R6For H, halogen atom or alkyl.
The acid is that Lewis acid or Bronsted acid, the dosage of the acid are calculated as the amount of isatin substance with the amount of substance 20%.
The Lewis acid is copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid yttrium, trifluoromethanesulfonic acid indium, trichlorine Change iron or copper bromide；Bronsted acid is trifluoromethanesulfonic acid, trifluoracetic acid, p-methyl benzenesulfonic acid, acetic acid or sulfuric acid.
The acid is trifluoracetic acid.
The organic solvent be acetonitrile, toluene, methanol, chloroform, dichloromethane, 1,2- dichloroethanes, tetrahydrofuran, 1, 4- dioxane or ethyl acetate.
The organic solvent is toluene.
The reaction temperature is 50 DEG C.
The molar ratio of the isatin, tetrahydroisoquinoline and 3- alkene Oxoindoles is 1:1:1-1:2:2.
The molar ratio of the isatin, tetrahydroisoquinoline and 3- alkene Oxoindoles is 1:1.2:1.2.
Beneficial effects of the present invention：The present invention is molten by the way that isatin, tetrahydroisoquinoline and 3- alkene Oxoindoles are added in toluene In agent, using trifluoracetic acid as catalyst, [3+2] cycloaddition reaction of three components occurs at a temperature of 50 DEG C to prepare double loop coils Oxoindole.The present invention introduces tetrahydroisoquinoline this physiological activity skeleton on the basis of double loop coil Oxoindole parent nucleus, Target product is obtained using the method treated different things alike, intermediate product is not required to isolate and purify, and target product can be easily separated；Operation letter List, reaction condition are mild, and yield is up to 91%.
Description of the drawings
Fig. 1 is 1 compound 4a's of embodiment1H NMR figures；
Fig. 2 is 1 compound 4a's of embodiment13C NMR figures；
Fig. 3 is the X-ray single crystal diffraction figure of 1 compound 4a of embodiment.
Specific implementation mode
With reference to specific embodiment, the present invention will be further described.It should be understood that following embodiment is merely to illustrate this The person skilled in the art of the range of invention and is not intended to limit the present invention, the field can make one according to the content of foregoing invention A little nonessential modifications and adaptations.
Embodiment 1
The preparation of tetrahydroisoquinoline and the double loop coil Oxoindole 4a of pyrrole skeleton：Into 10mL hard glass reaction tubes, N-methyl-isatin (0.2mmol, 32.2mg), tetrahydroisoquinoline (0.24mmol, 32.0mg), 3- alkene Oxoindoles is added (0.24mmol, 72.8mg) and trifluoroacetic acid (0.04mmol, 2.9uL), is then added 1mL toluene, and mixture is stirred at 50 DEG C 72h.After the reaction was complete, toluene is removed under reduced pressure, and pass through column chromatography separating purification, petroleum ether:Ethyl acetate (v:V)=20:1, Obtain target compound 4a (white solid, yield 76%).
The nuclear magnetic resonance spectroscopy of gained compound 4a, carbon spectrum, infrared and high resolution mass spectrum data are as follows:
1H NMR(400MHz,CDCl3), δ 8.15 (d, J=8.0Hz, 1H), 7.95 (d, J=8.0Hz, 1H), 7.54 (d, J =8.0Hz, 1H), 7.37 (q, J=8.0Hz, 2H), 7.27 (t, J=8.0Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 7.02 (s, 2H), 6.87 (d, J=8.0Hz, 2H), 6.41 (d, J=8.0Hz, 1H), 5.75 (s, 1H), 4.33 (s, 1H), 3.32 (s, 3H),3.10-2.99(m,4H),2.71-2.55(m,3H),1.55(s,9H)；13C NMR(100MHz,CDCl3)δ176.7, 175.9,168.2,149.2,144.9,139.6,134.9,134.6,129.9(2C),129.3,128.7,126.6,126.5, 125.5,125.3,125.2,124.5,123.0,122.8,114.7,108.0,84.0,70.3,69.9,63.8,58.4, 51.3,41.6,29.7,28.0,26.0.IR(KBr)ν2980,2941,1771,1736,1721,1296,1154,751cm- 1.HRMS(ESI)calcd for C34H34N3O6 +[M+H]+580.2442,found 580.2445.
For the preparation method of compound 4b-y with compound 4a, rate of charge is identical as compound 4a, and compound 4b-y can be obtained, Reaction yield is shown in Table 1 to table 2, but it needs to be emphasized that the compound of the present invention is not limited to chemical combination shown in table 1 to table 2 Object.
Table 1：The structure of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton
Table 2：The structure of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton
Compound 4b (white solid, 91% yield)：1H NMR(400MHz,CDCl3), δ 7.65 (d, J=8.0Hz, 1H), 7.41(dd,J1=J2=8.0Hz, 2H), 7.24-6.96 (m, 8H), 6.55 (d, J=8.0Hz, 1H), 5.97 (d, J=4.0Hz, 1H), 3.99 (d, J=8.0Hz, 1H), 3.60 (q, J=8.0Hz, 1H), 3.39 (s, 3H), 3.14-3.04 (m, 2H), 2.89- 2.84 (m, 1H), 2.72 (d, J=16.0Hz, 1H), 2.59 (t, J=8.0Hz, 1H), 1.52 (s, 9H), 0.72 (t, J= 8.0Hz,3H)；13C NMR(100MHz,CDCl3)δ175.2,173.7,171.3,148.7,143.8,139.7,137.7, 134.4,129.9,129.0,128.8,126.6,126.3,125.7,124.9,123.8,123.6,123.4,122.3, 114.0,107.6,one carbon missing in the aromatic region,83.7,77.6,62.2,60.7, 55.0,51.6,42.7,33.7,29.6,27.9,12.1.IR(KBr)ν2979,2935,1738,1701,1474,1360, 1163,747cm-1.HRMS(ESI)calcd for C35H36N3O6 +[M+H]+594.25986,found 594.25970.
Compound 4c (white solid, 75% yield)：1H NMR(400MHz,CDCl3), δ 7.67 (d, J=8.0Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 7.22-7.08 (m, 6H), 7.04-6.96 (m, 2H), 6.51 (d, J=8.0Hz, 1H), 5.97 (d, J=12.0Hz, 1H), 5.29-5.20 (m, 1H), 4.87 (d, J=12.0Hz, 1H), 4.51 (d, J=16.0Hz, 1H), 4.29-4.23 (m, 1H), 3.99 (d, J=8.0Hz, 1H), 3.66 (dd, J1=4.0Hz, J2=8.0Hz, 1H), 3.38 (s, 3H),3.11-3.05(m,1H),2.90-2.83(m,1H),2.72(dd,J1=J2=4.0Hz, 1H), 2.60 (dd, J1=J2= 4.0Hz,1H),1.52(s,9H)；13C NMR(100MHz,CDCl3)δ175.2,173.7,171.3,148.7,144.0, 139.8,137.6,134.4,130.6,129.9,129.1,128.8,126.5,126.4(2C),125.8,125.0,123.8 (2C),123.1,122.5,117.0,114.1,108.5,83.8,77.8,62.1,60.7,55.1,51.6,42.8,41.4, 29.6,28.0.IR(KBr)ν3449,2938,1739,1705,1473,1359,1298,1162,747cm-1.HRMS(ESI)m/z calcd for C36H36N3O6 +[M+H]+606.2599,found 606.2595.
Compound 4d (white solid, 76% yield)：1H NMR(400MHz,CDCl3), δ 7.70 (d, J=8.0Hz, 1H), 7.43(dd,J1=J2=8.0Hz, 2H), 7.23 (d, J=8.0Hz, 1H), 7.13-7.04 (m, 8H), 6.99-6.91 (m, 2H), 6.54 (d, J=8.0Hz, 2H), 6.30 (d, J=8.0Hz, 1H), 5.97 (d, J=12.0Hz, 1H), 4.89 (d, J= 16.0Hz, 1H), 4.22 (d, J=16.0Hz, 1H), 3.99 (d, J=8.0Hz, 1H), 3.35 (s, 3H), 3.10-2.99 (m, 1H),2.89-2.82(m,1H),2.71(dd,J1=J2=4.0Hz, 1H), 2.57 (dd, J1=J2=8.0Hz, 1H), 1.48 (s,9H)；13C NMR(100MHz,CDCl3)δ175.3,173.9,171.2,148.7,144.0,139.9,137.5,134.9, 134.3,130.0,129.2,128.8,128.6,127.2,126.7,126.6,126.4(2C),125.8,125.0,124.0, 123.9,123.2,122.6,114.2,108.8,83.8,77.5,62.0,60.6,55.3,51.6,43.0,42.7,29.6, 27.9.IR(KBr)ν3437,2924,1767,1736,1467,1355,1294,1161,754cm-1.HRMS(ESI)calcd for C40H38N3O6 +[M+H]+656.2755,found 656.2754.
Compound 4e (white solid, 71% yield)：1H NMR(400MHz,CDCl3), δ 7.70 (d, J=8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.23-7.02 (m, 7H), 6.94 (t, J=8.0Hz, 1H), 6.45 (dd, J1=J2=4.0Hz, 1H), 5.97 (d, J=8.0Hz, 1H), 3.95 (d, J=8.0Hz, 1H), 3.39 (s, 3H), 3.15-3.06 (m, 1H), 2.91- 2.86 (m, 1H), 2.74 (s, 4H), 2.60 (t, J=8.0Hz, 1H), 1.54 (s, 9H)；13C NMR(100MHz,CDCl3)δ 175.0,173.9,171.1,158.9 (d, J=240.0Hz, 1C), 148.8,140.6,139.7,137.4,134.2,129.3, (128.9,126.4,126.0,125.8,125.0,124.9,123.6,123.4,116.3 d, J=24.0Hz, 1C), 114.5 (d, J=26.0Hz, 1C), 114.1,108.1 (d, J=8.0Hz, 1C), 84.2,77.9,62.2,60.9,54.9,51.7, 42.9,29.6,27.7,25.3.IR(KBr)ν3406,2973,2924,2850,1760,1615,1490,1351,1300, 1165,761cm-1.HRMS(ESI)calcd for C34H33FN3O6 +[M+H]+598.2348,found 598.2350.
Compound 4f (white solid, 70% yield)：1H NMR(400MHz,CDCl3), δ 8.09 (d, J=8.0Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 7.54 (d, J=4.0Hz, 1H), 7.41-7.24 (m, 3H), 7.05 (d, J=8.0Hz, 2H), 6.91-6.86 (m, 1H), 6.80 (d, J=8.0Hz, 1H), 6.39 (d, J=12.0Hz, 1H), 5.72 (s, 1H), 4.27 (s, 1H),3.31(s,3H),3.13-3.05(m,1H),3.01(s,3H),2.69-2.57(m,3H),1.56(s,9H)；13C NMR (100MHz,CDCl3)δ176.5,175.6,168.2,149.2,143.5,139.6,134.8,134.4,130.0,129.7, 129.4,128.9,128.5,128.3,126.6,125.6,125.3,125.1,125.0,123.0,114.8,109.1,84.2, 70.2,69.9,64.0,58.2,51.5,41.7,29.6,28.0,26.2.IR(KBr)ν3428,2943,1723,1487, 1294,1154,755cm-1.HRMS(ESI)m/z calcd for C34H33ClN3O6 +[M+H]+614.2052,found 614.2054.
Compound 4g (white solid, 73% yield)：1H NMR(400MHz,CDCl3), δ 8.09 (d, J=8.0Hz, 1H), 7.95 (d, J=8.0Hz, 1H), 7.45 (d, J=8.0Hz, 1H), 7.38 (t, J=8.0Hz, 1H), 7.26 (t, J=8.0Hz, 1H),7.09(dd,J1=J2=4.0Hz, 1H), 7.04-7.02 (m, 2H), 6.90-6.86 (m, 2H), 6.39 (d, J=4.0Hz, 1H),5.71(s,1H),4.28(s,1H),3.30(s,3H),3.06-3.04(m,1H),3.01(s,3H),2.72-2.57(m, 3H),1.55(s,9H)；13C NMR(100MHz,CDCl3)δ176.7,175.9,168.3,149.2,146.1,139.6, 135.9,134.9,134.5,129.7,129.4,128.9,126.6,125.6(2C),125.3,125.2,125.1,123.0, 122.7,114.8,108.9,84.2,70.0,69.9,63.9,58.3,51.5,41.6,29.7,28.0,26.2.IR(KBr)ν 3435,2940,1720,1607,1488,1363,1294,1152,757cm-1.HRMS(ESI)calcd for C34H33ClN3O6 + [M+H]+614.2052,found 614.2056.
Compound 4h (white solid, 73% yield)：1H NMR(400MHz,CDCl3), δ 8.09 (d, J=8.0Hz, 1H), 7.95 (d, J=8.0Hz, 1H), 7.45 (d, J=8.0Hz, 1H), 7.39 (t, J=8.0Hz, 1H), 7.27 (t, J=8.0Hz, 2H), 7.06-7.00 (m, 3H), 6.91-6.86 (m, 1H), 6.40 (d, J=8.0Hz, 1H), 5.70 (s, 1H), 4.26 (s, 1H),3.69(s,3H),3.11-3.06(m,1H),3.02(s,3H),2.67-2.56(m,3H),1.55(s,9H)；13C NMR (100MHz,CDCl3)δ176.6,176.2,168.2,149.2,140.8,139.6,134.9,134.6,132.3,129.8, 129.7,129.4,128.9,126.6,125.6,125.3,125.2,123.6,123.1,123.0,115.4,114.8,84.2, 69.9,69.7,64.3,58.1,51.5,41.6,29.7,29.3,28.0.IR(KBr)ν3430,2983,2916,2831, 1746,1701,1601,1483,993,836,761cm-1.HRMS(ESI)calcd for C34H33ClN3O6 +[M+H]+ 614.2052,found 614.2053.
Compound 4i (white solid, 69% yield)：1H NMR(400MHz,CDCl3), δ 8.09 (d, J=8.0Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 7.67 (s, 1H), 7.48 (d, J=8.0Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 7.28 (s, 1H), 7.03 (s, 2H), 6.88 (s, 1H), 6.75 (d, J=8.0Hz, 1H), 6.39 (d, J=4.0Hz, 1H), 5.71 (s, 1H),4.26(s,1H),3.30(s,3H),3.20-3.06(m,1H),3.01(s,3H),2.69-2.57(m,3H),1.55(s, 9H)；13C NMR(100MHz,CDCl3)δ176.5,175.5,168.2,149.2,144.0,139.7,134.9,134.5, 132.9,129.7,129.4,128.9,128.8,127.7,126.6,125.6,125.3,125.2,123.0,115.5, 114.8,109.5,84.2,70.2,69.9,64.0,58.2,51.5,41.7,29.7,28.0,26.2.IR(KBr)ν3407, 2939,1735,1713,1606,1481,1357,1290,1246,1153,1100,762cm-1.HRMS(ESI)calcd for C34H33BrN3O6 +[M+H]+658.1547,found 658.1549.
Compound 4j (white solid, 73% yield)：1H NMR(400MHz,CDCl3), δ 8.08 (d, J=8.0Hz, 1H), 7.95 (d, J=8.0Hz, 1H), 7.39 (t, J=8.0Hz, 2H), 7.26 (t, J=8.0Hz, 2H), 7.03 (d, J=8.0Hz, 3H), 6.90-6.86 (m, 1H), 6.39 (d, J=4.0Hz, 1H), 5.71 (s, 1H), 4.27 (s, 1H), 3.30 (s, 3H), 3.10-3.03(m,1H),3.01(s,3H),2.72-2.56(m,3H),1.55(s,9H)；13C NMR(100MHz,CDCl3)δ 176.6,175.9,168.2,149.2,146.3,139.7,134.9,134.5,129.8,129.3,128.9,126.6, 125.9,125.7(2C),125.6,125.3,125.2,123.8,123.1,114.8,111.6,84.2,70.1,70.0, 63.9,58.3,51.5,41.7,29.7,28.0,26.2.IR(KBr)ν3435,2978,2940,1723,1604,1485, 1362,1294,1154,757cm-1.HRMS(ESI)calcd for C34H33BrN3O6 +[M+H]+658.1547,found 658.1549.
Compound 4k (white solid, 48% yield)：1H NMR(400MHz,CDCl3), δ 8.15 (d, J=8.0Hz, 1H), 7.96 (d, J=8.0Hz, 1H), 7.38 (t, J=8.0Hz, 2H), 7.25 (t, J=8.0Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 7.02 (d, J=4.0Hz, 2H), 6.90-6.85 (m, 1H), 6.76 (d, J=8.0Hz, 1H), 6.41 (d, J=8.0Hz, 1H),5.74(s,1H),4.31(s,1H),3.30(s,3H),3.13-3.04(m,1H),3.00(s,3H),2.70-2.56(m, 3H),2.34(s,3H),1.55(s,9H)；13CNMR(100MHz,CDCl3)δ176.9,175.9,168.3,149.3,142.6, 139.6,135.0,134.8,132.5,130.2,130.0,129.3,128.7,126.6,126.5,125.5,125.3(2C), 125.2,123.1,114.7,107.7,84.1,70.4,70.0,63.8,58.4,51.3,41.6,29.7,28.0,26.0, 20.9.IR(KBr)ν3446,2980,2939,2820,1768,1736,1708,1492,1358,1293,1154,760cm- 1.HRMS(ESI)calcd for C35H36N3O6 +[M+H]+594.2599,found 594.2600.
Compound 4l (white solid, 67% yield)：1H NMR(400MHz,CDCl3), δ 8.15 (d, J=8.0Hz, 1H), 7.96 (d, J=8.0Hz, 1H), 7.37 (t, J=8.0Hz, 1H), 7.26 (t, J=8.0Hz, 1H), 7.21 (s, 1H), 7.03 (d, J=4.0Hz, 2H), 6.88-6.85 (m, 2H), 6.40 (d, J=8.0Hz, 1H), 5.72 (s, 1H), 4.26 (s, 1H), 3.57(s,3H),3.12-3.04(m,1H),3.00(s,3H),2.72-2.59(m,3H),2.56(s,3H),2.28(s,3H), 1.55(s,9H)；13C NMR(100MHz,CDCl3)δ176.9,176.5,168.3,149.3,140.2,139.6,135.0, 134.9,134.2,132.3,130.1,129.3,128.7,127.4,126.4,125.5,125.3,125.2,123.1, 123.0,119.2,114.7,84.1,69.9,69.6,64.2,58.2,51.3,41.5,29.7,29.3,28.0,20.6, 18.8.IR(KBr)ν3447,2982,2940,1737,1701,1477,1357,1294,1154,1095,759cm-1.HRMS (ESI)calcd for C36H38N3O6 +[M+H]+608.2755,found 608.2753.
Compound 4m (white solid, 72% yield)：1H NMR(400MHz,CDCl3), δ 8.17 (d, J=8.0Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 7.37 (t, J=8.0Hz, 1H), 7.26 (t, J=8.0Hz, 1H), 7.14 (d, J=4.0Hz, 1H), 7.02 (d, J=4.0Hz, 2H), 6.91-6.85 (m, 2H), 6.77 (d, J=12.0Hz, 1H), 6.40 (d, J=8.0Hz, 1H),5.75(s,1H),4.29(s,1H),3.81(s,3H),3.30(s,3H),3.13-3.05(m,1H),3.00(s,3H), 2.73-2.64 (m, 2H), 2.58 (d, J=16.0Hz, 1H), 1.56 (s, 9H)；13C NMR(100MHz,CDCl3)δ176.8, 175.7,168.2,156.4,149.2,139.6,138.4,135.0,134.8,130.0,129.4,128.7,128.0, 126.5,125.6,125.5,125.3,123.1,115.2,114.7,111.0,108.6,84.2,70.7,70.0,64.0, 58.4,55.9,51.3,41.7,29.7,28.0,26.1.IR(KBr)ν3394,2942,2829,1707,1607,1494, 1360,1158,1035,760cm-1.HRMS(ESI)calcd for C35H36N3O7 +[M+H]+610.2548,found 610.2544.
Compound 4n (white solid, 89% yield)：1H NMR(400MHz,CDCl3), δ 8.16 (d, J=8.0Hz, 1H), 7.95 (d, J=8.0Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.38 (q, J=8.0Hz, 2H), 7.33 (d, J=8.0Hz, 1H), 7.28 (t, J=8.0Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.88 (d, J=8.0Hz, 1H), 6.78 (t, J= 8.0Hz, 1H), 6.39 (d, J=8.0Hz, 1H), 5.74 (s, 1H), 4.32 (s, 1H), 3.33 (s, 3H), 3.00 (s, 3H), 2.91-2.85(m,1H),2.77-2.61(m,3H),1.57(s,9H)；13C NMR(100MHz,CDCl3)δ176.4,175.8, 168.1,149.1,144.9,139.5,137.3,134.9,130.8,130.1,129.6,128.9,126.8,126.4, 125.8,125.4,125.3,124.5,122.9,122.2,114.8,108.1,84.3,70.0,69.7,63.9,58.2, 51.4,41.3,31.0,28.0,26.0.IR(KBr)ν3448,2978,2942,2826,1716,1610,1472,1361, 1295,1248,1153,759cm-1.HRMS(ESI)calcd for C34H33BrN3O6 +[M+H]+658.1547,found 658.1549.
Compound 4o (white solid, 75% yield)：1H NMR(400MHz,CDCl3), δ 8.11 (d, J=8.0Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.37 (q, J=8.0Hz, 2H), 7.27 (t, J=8.0Hz, 1H), 7.19 (s, 1H), 7.11 (t, J=8.0Hz, 1H), 7.00 (dd, J1=J2=4.0Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.25 (d, J=8.0Hz, 1H), 5.67 (s, 1H), 4.30 (s, 1H), 3.32 (s, 3H), 3.07-3.03 (m, 1H), 3.00 (s,3H),2.75-2.53(m,3H),1.57(s,9H)；13C NMR(100MHz,CDCl3)δ176.5,176.0,168.2, 149.1,144.9,139.5,137.5,133.7,132.1,130.1,129.6,128.9,128.6,126.4,125.3, 124.9,124.6,122.9,120.3,114.8,108.1,one carbon missing in the aromatic region,84.4,70.3,69.5,63.6,58.4,51.4,41.2,29.6,28.0,26.1.IR(KBr)ν3442,2977, 2941,1717,1609,1476,1361,1294,1248,1153,758cm-1.HRMS(ESI)calcd for C34H33BrN3O6 + [M+H]+658.1547,found 658.1544.
Compound 4p (white solid, 41% yield)：1H NMR(400MHz,CDCl3), δ 8.15 (d, J=8.0Hz, 1H), 8.02 (d, J=8.0Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.42-7.34 (m, 2H), 7.29 (t, J=8.0Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 7.03 (d, J=4.0Hz, 2H), 6.90-6.86 (m, 2H), 6.36 (d, J=8.0Hz, 1H), 5.78(s,1H),4.45-4.35(m,2H),4.31(s,1H),3.32(s,3H),3.07-3.02(m,1H),3.00(s,3H), 2.75-2.56 (m, 3H), 1.36 (t, J=8.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ176.8,176.0,168.2, 150.8,145.0,139.3,135.0,134.5,130.0(2C),129.4,128.9,126.7,126.6,125.8,125.6, 125.4,124.5,123.0,122.9,114.8,108.1,70.2,69.8,64.2,63.3,58.4,51.4,41.6,29.9, 26.0,14.2.IR(KBr)ν3422,2940,1721,1611,1473,1362,1293,1234,756cm-1.HRMS(ESI) calcd for C32H30N3O6 +[M+H]+552.2129,found 552.2128.
Compound 4q (white solid, 47% yield)：1H NMR(400MHz,CDCl3), δ 8.17 (d, J=8.0Hz, 1H), 8.02 (d, J=8.0Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.39-7.28 (m, 8H), 7.13 (t, J=8.0Hz, 1H), 7.04 (d, J=4.0Hz, 2H), 6.88 (d, J=8.0Hz, 1H), 6.82-6.78 (m, 1H), 6.36 (d, J=8.0Hz, 1H), 5.80 (s, 1H), 5.45 (d, J=12.0Hz, 1H), 5.35 (d, J=12.0Hz, 1H), 4.33 (s, 1H), 3.33 (s, 3H), 3.11-3.03(m,1H),3.00(s,3H),2.74-2.57(m,3H)；13C NMR(100MHz,CDCl3)δ176.6,176.0, 168.1,150.7,145.0,139.2,135.1,135.0,134.5,130.0,129.9,129.4,128.9,128.5, 128.2,127.7,126.6,125.8,125.6,125.4,124.5,122.9(2C),114.8,108.1,one carbon missing in the aromatic region,70.2,69.9,68.3,64.1,58.4,51.4,41.6,29.8, 26.0.IR(KBr)ν3039,2931,1738,1718,1469,1343,1292,1229,1154,756cm-1.HRMS(ESI)m/z calcd for C37H32N3O6 +[M+H]+614.2286,found 614.2284.
Compound 4r (white solid, 58% yield)：1H NMR(400MHz,CDCl3), δ 8.15 (d, J=8.0Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 7.90 (d, J=8.0Hz, 2H), 7.47 (d, J=8.0Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.29 (t, J=4.0Hz, 1H), 7.22 (d, J=8.0Hz, 2H), 7.11 (t, J= 8.0Hz, 1H), 6.94 (d, J=8.0Hz, 1H), 6.86 (dd, J1=4.0Hz, J2=8.0Hz, 2H), 6.32 (t, J=8.0Hz, 1H), 5.98 (d, J=8.0Hz, 1H), 5.71 (s, 1H), 4.17 (s, 1H), 3.29 (s, 3H), 3.01-2.95 (m, 1H), 2.92 (s,3H),2.68-2.51(m,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ176.6,175.8,167.8, 145.3,144.9,139.1,135.3,134.7,134.0,130.1,129.8,129.6,129.1,129.2,127.9, 126.4,126.0(2C),125.7,125.6,124.5,122.9,122.6,113.0,108.1,70.2,69.3,64.4, 58.0,51.4,41.6,29.7,26.0,21.7.IR(KBr)ν3412,2922,1748,1710,1608,1464,1374, 1183,1148,1084,753cm-1.HRMS(ESI)calcd for C36H32N3O6S+[M+H]+634.2006,found 634.2000.
Compound 4s (white solid, 83% yield)：1H NMR(400MHz,CDCl3),δ10.51(s,1H),8.44(d,J =8.0Hz, 1H), 8.19 (d, J=4.0Hz, 1H), 7.54 (dd, J1=J2=8.0Hz, 3H), 7.43 (dd, J1=8.0Hz, J2 =4.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.36-7.31 (m, 3H), 7.18-7.10 (m, 2H), 7.05 (t, J= 8.0Hz,2H),6.91(dd,J1=J2=8.0Hz, 2H), 6.39 (d, J=8.0Hz, 1H), 5.86 (s, 1H), 4.27 (s, 1H), 3.34 (s, 3H), 3.14-3.08 (m, 1H), 3.01 (s, 3H), 2.71 (d, J=8.0Hz, 2H), 2.63 (d, J=16.0Hz, 1H)；13C NMR(100MHz,CDCl3)δ181.6,175.7,167.8,149.2,145.0,140.0,137.1,134.7, 134.5,130.2,129.6,129.5,129.2,129.0,126.9,126.5,126.3,125.8,125.2,124.4, 124.2,123.0,122.8,120.4,116.3,108.2,70.2,69.5,64.2,58.9,51.6,41.7,29.7, 26.1.IR(KBr)ν3245,2931,1721,1606,1551,1156,749cm-1.HRMS(ESI)calcd for C36H31N4O5 [M+H]+599.2289,found 599.2283.
Compound 4t (white solid, 72% yield)：1H NMR(400MHz,CDCl3),δ10.53(s,1H),8.46(d,J =8.0Hz, 1H), 8.27 (d, J=8.0Hz, 1H), 7.56 (dd, J1=J2=8.0Hz, 3H), 7.46-7.33 (m, 5H), 7.18-7.04 (m, 4H), 6.91 (t, J=8.0Hz, 2H), 6.39 (d, J=4.0Hz, 1H), 5.87 (s, 1H), 4.29 (s, 1H),3.58-3.49(m,2H),3.35(s,3H),3.15-3.07(m,1H),2.68(dd,J1=8.0Hz, J2=16.0Hz, 3H), 0.56 (t, J=8.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ181.7,175.7,167.2,149.1,145.0, 140.2,137.1,134.7,134.6,130.1,129.8,129.5,129.2,129.0,126.8,126.5,126.2, 125.8,125.5,124.3,124.2,122.9,122.8,120.3,116.3,108.2,70.2,69.6,64.1,60.9, 58.9,41.7,29.7,26.1,13.1.IR(KBr)ν3257,2927,1721,1607,1549,754cm-1.HRMS(ESI) calcd for C37H33N4O5 +[M+H]+613.2446,found 613.2447.
Compound 4u (white solid, 63% yield)：1H NMR(400MHz,CDCl3), δ 8.19 (d, J=8.0Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.35 (q, J=8.0Hz, 2H), 7.26 (t, J=8.0Hz, 1H), 7.15-7.09 (m, 1H), 7.03-7.02 (m, 2H), 6.87 (t, J=8.0Hz, 2H), 6.39 (d, J=8.0Hz, 1H), 5.74(s,1H),4.32(s,1H),3.51-3.48(m,2H),3.32(s,3H),3.09-3.04(m,1H),2.71-2.56(m, 3H), 1.56 (s, 9H), 0.54 (t, J=8.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ176.9,176.0,167.7, 149.2,145.0,139.8,135.0,134.7,130.1,129.9,129.3,128.7,126.8,126.5,125.6(2C), 125.3,124.6,123.1,122.8,114.7,108.0,84.1,70.3,70.1,63.9,60.6,58.4,41.7,29.7, 28.0,26.0,13.1.IR(KBr)ν2980,2934,1724,1473,1296,1155,755cm-1.HRMS(ESI)calcd for C35H36N3O6[M+H]+594.2599,found 594.2593.
Compound 4v (white solid, 53% yield)：1H NMR(400MHz,CDCl3), δ 8.02 (d, J=8.0Hz, 1H), 7.96(dd,J1=J2=4.0Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.37 (t, J=8.0Hz, 1H), 7.13-7.03 (m, 4H), 6.88 (d, J=8.0Hz, 2H), 6.37 (d, J=8.0Hz, 1H), 5.70 (s, 1H), 4.31 (t, J=8.0Hz, 1H), 3.32(s,3H),3.08-3.01(m,4H),2.71-2.56(m,3H),1.54(s,9H)；13C NMR(100MHz,CDCl3)δ (176.4,175.9,168.0,160.4 d, J=243.0Hz, 1C), 149.2,145.1,135.6 (d, J=3.0Hz, 1C), (135.1,134.4,132.1 d, J=9.0Hz, 1C), 130.1,129.5,126.7,126.5,125.7,124.6,123.0 (d, J=12.0Hz, 1C), 116.1 (d, J=8.0Hz, 1C), 115.5,115.3,113.1 (d, J=25.0Hz, 1C), 108.2, 84.4,70.4,70.2,63.6,58.7,51.6,41.7,29.7,28.1,26.1.IR(KBr)ν3431,2927,1736, 1717,1481,1296,1151,753cm-1.HRMS(ESI)calcd for C34H33FN3O6[M+H]+598.2348, found598.2349.
Compound 4w (white solid, 34% yield)：1H NMR(400MHz,CDCl3), δ 8.22 (d, J=4.0Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.38-7.35 (m, 2H), 7.11 (t, J=8.0Hz, 1H), 7.04 (d, J=8.0Hz, 2H), 6.88 (d, J=8.0Hz, 2H), 6.36 (d, J=8.0Hz, 1H), 5.70 (s, 1H), 4.32 (s,1H),3.32(s,3H),3.09-3.01(m,4H),2.73-2.55(m,3H),1.54(s,9H)；13C NMR(100MHz, CDCl3)δ176.1,175.7,167.9,149.0,145.1,138.2,135.0,134.3,131.9,130.7,130.1, 129.4,128.9,126.7,126.4,125.6(2C),124.5,122.9,122.8,116.0,108.1,84.5,70.3, 70.1,63.5,58.4,51.5,41.6,29.7,28.0,26.1.IR(KBr)ν3429,2927,1736,1714,1470, 1340,1295,1155,752cm-1.HRMS(ESI)calcd for C34H33ClN3O6[M+H]+614.2052,found 614.2055.
Compound 4x (white solid, 42% yield)：1H NMR(400MHz,CDCl3), δ 8.35 (d, J=4.0Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 7.54-7.51 (m, 2H), 7.36 (t, J=8.0Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 7.04 (d, J=8.0Hz, 2H), 6.88 (d, J=8.0Hz, 2H), 6.36 (d, J=8.0Hz, 1H), 5.69 (s, 1H), 4.31 (s,1H),3.32(s,3H),3.09-3.00(m,4H),2.72-2.55(m,3H),1.54(s,9H)；13C NMR(100MHz, CDCl3)δ176.0,175.7,167.9,149.0,145.1,138.8,135.1,134.3,132.3,131.9,130.1, 129.4,128.4,126.7,126.5,125.6,124.5,123.0,122.8,118.2,116.4,108.1,84.5,70.3, 70.1,63.5,58.3,51.6,41.6,29.7,28.0,26.1.IR(KBr)ν3440,2941,1738,1713,1469, 1339,1295,1155,752cm-1.HRMS(ESI)calcd for C34H33BrN3O6[M+H]+658.1547,found 658.1541.
Compound 4y (white solid, 60% yield)：1H NMR(400MHz,CDCl3),δ7.94(s,1H),7.83(d,J =8.0Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 7.01 (s, 2H), 6.86 (d, J=4.0Hz, 2H), 6.40 (d, J=8.0Hz, 1H), 5.71 (s, 1H),4.33(s,1H),3.32(s,3H),3.09-3.02(m,4H),2.71-2.55(m,3H),2.40(s,3H),1.55(s, 9H)；13C NMR(100MHz,CDCl3)δ176.9,175.8,168.3,149.2,145.0,137.2,134.9,134.8, 134.7,129.9(2C),129.3,129.2,126.7,126.4,125.6,125.5,124.6,123.1,122.7,114.5, 107.9,83.9,70.2,69.9,63.7,58.4,51.3,41.6,29.7,28.0,26.0,21.3.IR(KBr)ν3419, 2940,1720,1486,1341,1295,1156,753cm-1.HRMS(ESI)calcd for C35H36N3O6[M+H]+ 594.2599,found 594.2598.
The basic principles and main features and advantages of the present invention of the present invention have been shown and described above.The skill of the industry Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and Its equivalent thereof.

Claims (10)

1. simultaneously the double loop coil Oxoindoles of pyrrole skeleton, structural formula are as follows for a kind of tetrahydroisoquinoline：
, wherein R1For alkyl；R2For H, halogen atom or alkyl；R3For halogen atom；R4For alcoxyl carbonyl Base or sulfonyl；R5For ester group；R6For H, halogen atom or alkyl.
2. the preparation method of tetrahydroisoquinoline according to claim 1 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：By various substitution isatin, tetrahydroisoquinoline and 3- alkene Oxoindoles, in organic solvent, in the presence of acid, 25-100oC reacts 24-72 h, and thin-layer chromatography tracking reaction is to complete, and after the reaction was complete, solvent evaporated by column chromatography or is separated by filtration Purifying, obtains target product, reaction formula is as follows：
；
Wherein, R1For alkyl；R2For H, halogen atom or alkyl；R3For halogen atom；R4For alkoxy carbonyl group or sulfonyl；R5For ester group； R6For H, halogen atom or alkyl.
3. the preparation method of tetrahydroisoquinoline according to claim 2 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The acid is that Lewis acid or Bronsted acid, the dosage of the acid are calculated as the 20% of the amount of isatin substance with the amount of substance.
4. the preparation method of tetrahydroisoquinoline according to claim 3 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The Lewis acid is copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid yttrium, trifluoromethanesulfonic acid indium, tri-chlorination Iron or copper bromide；Bronsted acid is trifluoromethanesulfonic acid, trifluoracetic acid, p-methyl benzenesulfonic acid, acetic acid or sulfuric acid.
5. the preparation method of tetrahydroisoquinoline according to claim 3 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The acid is trifluoracetic acid.
6. the preparation method of tetrahydroisoquinoline according to claim 2 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The organic solvent is acetonitrile, toluene, methanol, chloroform, dichloromethane, 1,2- dichloroethanes, tetrahydrofuran, 1,4- Dioxane or ethyl acetate.
7. the preparation method of tetrahydroisoquinoline according to claim 2 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The organic solvent is toluene.
8. the preparation method of tetrahydroisoquinoline according to claim 2 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The reaction temperature is 50oC。
9. the preparation method of tetrahydroisoquinoline according to claim 2 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The molar ratio of the isatin, tetrahydroisoquinoline and 3- alkene Oxoindoles is 1:1:1-1:2:2.
10. the preparation method of tetrahydroisoquinoline according to claim 9 and the double loop coil Oxoindoles of pyrrole skeleton, feature It is：The molar ratio of the isatin, tetrahydroisoquinoline and 3- alkene Oxoindoles is 1:1.2:1.2.
CN201810354461.7A 2018-04-19 2018-04-19 A kind of tetrahydroisoquinoline and the double loop coil Oxoindoles of pyrrole skeleton and preparation method thereof Pending CN108440530A (en)

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