CN111018864A - Preparation method of indole-fused octamer lactam compound - Google Patents

Preparation method of indole-fused octamer lactam compound Download PDF

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CN111018864A
CN111018864A CN201911350220.6A CN201911350220A CN111018864A CN 111018864 A CN111018864 A CN 111018864A CN 201911350220 A CN201911350220 A CN 201911350220A CN 111018864 A CN111018864 A CN 111018864A
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钱鹏程
叶龙武
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Baoyuan Chemical Industry Co ltd
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Institute of New Materials and Industrial Technology of Wenzhou University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a preparation method of an indole-fused octamer lactam compound. The method takes the indolyl alkynylamide compound as a raw material, prepares and obtains a series of indole condensed octamer lactam compounds in the presence of a zinc catalyst and an N-oxide oxidant, and has the advantages of no need of using a noble metal catalyst, easy operation of reaction, mild and simple conditions, wide substrate application range and high yield of target products.

Description

Preparation method of indole-fused octamer lactam compound
Technical Field
The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an indole fused octamer lactam compound.
Background
Mesolactams, especially indole-fused mesolactams such as Paullone and its derivatives and Balasubramide et al (see formula I below), are important building blocks found in a large number of natural products and bioactive molecules. However, it is often difficult to form these backbones because of the entropic effects that should interact with the trans-ring. The synthetic methods reported to date are very limited and most are limited to noble metal catalysis. Therefore, there is an urgent need to develop novel construction strategies, especially those with high efficiency and flexibility.
The method comprises the following steps:
Figure BDA0002334465740000011
in the past decade, the oxidation of alkyne intermolecular N-O bond oxidants through gold catalyzed oxidation to the putative α -oxo gold carotenoid intermediates has attracted considerable research interest because this approach avoids the use of the hazardous, unavailable and potentially explosive species α -diazocarbonyl compounds as precursors for carbene generation.
Although the preparation of larger lactam ring compounds remains challenging compared to five or six membered lactams that we have reported in our subject group, with these results and our recent studies on mesolactam-catalyzed synthesis ((a) nat. commun.2019,10,3234, (b) angelw. chem. int. ed.2017,56, 4015-. In the present invention, we disclose a zinc-catalyzed strategy for oxidative cyclization of indolenine amides to rapidly and practically produce a variety of valuable mesolactams (seven-or eight-membered lactams).
Disclosure of Invention
The invention aims to provide a preparation method of an indole-fused octamembered lactam compound. According to the method, a series of indole condensed octamer lactams are prepared by taking indole alkyne amide compounds as raw materials in the presence of a zinc catalyst and an N-oxide oxidant, and the method does not need to use a noble metal catalyst, is easy to operate in reaction, mild and simple in condition, wide in substrate application range and high in target product yield.
The invention provides a preparation method of an indole fused octa-lactam compound, which comprises the following steps: adding auxiliary agent NaBAr into the reactor in sequenceF 4Catalyst zinc triflate (Zn (OTf)2) An indolyalkynylamide compound shown as a formula I and an N-oxide oxidant, and then adding an organic solventReplacing the reactor with inert atmosphere, heating and stirring at 40-100 ℃ for reaction, monitoring the reaction by TLC, concentrating the reaction solution to obtain a residue, and separating by silica gel column chromatography to obtain the indole fused octamer lactam compound shown in formula III.
Figure BDA0002334465740000031
Wherein, in formula I and formula III, R1Represents one or more substituents on the attached phenyl ring, each R1The substituents are independently of one another selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl radical, C1-6Acyl, -CN, -NO2。
R2Represents substituted or unsubstituted C6-14An aryl group; wherein the "substituents" in this expression substituted or unsubstituted are selected from halogen, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl radical, C1-6Acyl, -CN, -NO2、-C(O)O C1-6Any one or more of alkyl.
PG1And PG2Represents a protecting group selected from any one of Ms (methylsulfonyl), Ts (p-toluenesulfonyl) and/or Bs (p-bromophenylsulfonyl).
The auxiliary agent NaBArF 4The structure is as follows:
Figure BDA0002334465740000032
the structure of the N-oxide oxidant is as follows:
Figure BDA0002334465740000033
and/or
Figure BDA0002334465740000034
Wherein, the substituent R in the formula II represents 2-Br,2-Cl, 3,5-Cl2,2,6-Br2,2,6-Cl2Any one of them.
According to the inventionIn the aforementioned preparation process, preferably, R in formula I and formula III1Represents one or more substituents on the attached phenyl ring, each R1The substituents are independently from each other selected from hydrogen, chlorine, bromine, methyl;
R2represents a substituted or unsubstituted phenyl group; wherein the "substituent" in this expression substituted or unsubstituted is selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy, aldehyde, -C (O) OMe, -CN, -NO2、-C(O)CH3Any one or more of them.
In the formula II, R preferably represents 2,6-Br2,2,6-Cl2Any one of the above; most preferably, R represents 2,6-Cl2。
In the above preparation method according to the present invention, the organic solvent is selected from Dichloroethane (DCE), and the amount of the organic solvent used is not particularly limited, but is generally 0.01 to 1mol/L based on the concentration of the raw material of formula I.
According to the foregoing preparation method of the present invention, the inert gas atmosphere is selected from a nitrogen atmosphere or an argon atmosphere. Preferably, the inert atmosphere is selected from a nitrogen atmosphere.
According to the aforementioned production method of the present invention, the reaction temperature is preferably 60 to 80 ℃, most preferably 80 ℃.
According to the preparation method of the invention, the reaction time of the heating and stirring reaction is 10min to 12h, and preferably the reaction time of the heating and stirring reaction is 0.5 h.
According to the preparation method, the indolyl alkynylamide compound shown in the formula I and the catalyst zinc trifluoromethanesulfonate (Zn (OTf)2) Auxiliary agent NaBArF 4The feeding molar ratio of the N-oxide oxidant to the N-oxide oxidant is 1 (0.05-0.2) to (0.1-0.4) to (1-3). Preferably, the indolyl alkynylamide compound shown as the formula I and the catalyst zinc trifluoromethanesulfonate (Zn (OTf)2) Auxiliary agent NaBArF 4And the feeding molar ratio of the N-oxide oxidant is 1 (0.1) to (0.2) to (2).
According to the preparation method of the present invention, the reaction mechanism can be represented by the following formula two:
the second formula:
Figure BDA0002334465740000051
the method of the invention achieves the following beneficial effects:
1) the invention reports that a series of indole condensed octa-lactam compounds are prepared by designing an indolyl alkynylamide compound as a raw material in the presence of a zinc catalyst and an N-oxide oxidant, and the defect that a larger ring lactam derivative is difficult to obtain by the method in the prior art is overcome compared with the method for synthesizing five-membered ring and/or six-membered ring lactam in the prior art.
2) The method does not need to use a noble metal catalyst, the reaction is easy to operate, the condition is mild and simple, the substrate application range is wide, and the yield of the target product is high. The use of readily available substrates, non-noble metals as catalysts and simple steps make the process very practical in organic synthesis. Furthermore, such asymmetric syntheses have also been achieved by using chiral substrates.
Detailed Description
The present invention will be described in more detail with reference to examples. Hereinafter, unless otherwise specified, the methods are all conventional in the art, and the reagents used are commercially available; the reaction raw materials can be prepared according to the preparation method known in the prior art and the existing synthesis conditions.
Reaction conditions optimization examples
The indolyl alkynylamide compound in the formula I-1 is used as a template to discuss the influence of different synthesis process condition changes on the reaction.
Example 1
Figure BDA0002334465740000061
Adding auxiliary agent NaBAr into a Schlenk tube-sealed reactor in sequenceF 4(0.04mmol,35.6mg), zinc trifluoromethanesulfonate catalyst (Zn (OTf)2)(0.02mmol,7.3mg), an indolyalkynylamide compound represented by the formula I-1 (0.20mmol) and an N-oxide oxidizing agent represented by the formula II (R ═ 2, 6-Cl)260.0mg,0.4mmol), followed by addition of an organic solvent DCE (dichloroethane, 2mL), replacement of the reactor with a nitrogen atmosphere, heating at 80 ℃ with stirring for 0.5h, monitoring completion of the reaction by TLC, concentration of the reaction solution to give a residue, separation by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate) to give an indole-fused octamembered lactam compound represented by the formula III-1. Yield: 92 percent. White solid (mp 225-.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.8Hz,1H),7.37–7.32(m,3H),7.31–7.26(m,1H),7.25–7.16(m,2H),7.11–7.06(m,1H),6.84(d,J＝8.0Hz,1H),5.51(s,1H),4.11–3.98(m,1H),3.82–3.73(m,1H),3.51–3.23(m,5H),3.17(s,3H),2.10–1.97(m,2H)；13C NMR(100MHz,CDCl3)δ174.0,135.9,134.3,128.9,128.7,128.6,128.0,125.0,123.7,120.2,117.5,114.5,53.7,42.8,42.5,41.6,28.5,20.0；IR(neat):2917,2849,1682(s),1454,1361,1262,1162,962,765,541；HRESIMS Calcd for[C21H22N2NaO5S2]+(M+Na+)469.0862,found 469.0863.。
Example 2
The reaction time of the oxidant (R ═ 2-Br,2equiv) shown in the formula II is 12h, and no auxiliary agent NaBAr is addedF 4The other conditions were the same as in example 1, yield 27%.
Example 3
An oxidant (R ═ 2-Cl,2equiv) shown in formula II, the reaction time is 12h, and an auxiliary agent NaBAr is not addedF 4The other conditions were the same as in example 1, yield 35%.
Example 4
An oxidizing agent of formula II (R ═ 3, 5-Cl)22equiv) for 4 hours without the addition of NaBAr as an auxiliaryF 4The other conditions were the same as in example 1, yield 32%.
Example 5
An oxidizing agent of formula II (R ═ 2, 6-Br)22equiv) for 0.5h without addition of NaBAr as an auxiliaryF 4The rest stripsThe same procedure as in example 1 was repeated, except that the yield was 54%.
Example 6
An oxidizing agent of formula II (R ═ 2, 6-Cl)22equiv) for 0.5h without addition of NaBAr as an auxiliaryF 4The other conditions were the same as in example 1, yield 58%.
Example 7
Use of oxidizing agent
Figure BDA0002334465740000071
(2equiv) the reaction time is 12h, and no auxiliary agent NaBAr is addedF 4The other conditions were the same as in example 1, yield: trace amounts.
Example 8
Catalyst replacement with copper triflate (Cu (OTf)2) (0.02mmol) without the addition of NaBAr as auxiliary agentF 4The other conditions were the same as in example 1, yield: 36 percent.
Example 9
Catalyst replacement with scandium triflate (Sc (OTf)3) (0.02mmol) without the addition of NaBAr as auxiliary agentF 4The other conditions were the same as in example 1, yield: 39 percent.
Example 10
No catalyst Zinc triflate (Zn (OTf))2) The reaction time is 1h, the rest conditions are the same as example 1, and the yield is 76%.
Example 11
No catalyst Zinc triflate (Zn (OTf))2) While MsOH (methanesulfonic acid) is used to replace NaBArF 4(0.04mmol) and the reaction time was 12 hours, the same procedure as in example 1 was repeated, thereby obtaining a yield of 10%.
Example 12
No catalyst Zinc triflate (Zn (OTf))2) Simultaneously with Tf2Replacement of NaBAr by NH (bis (trifluoromethanesulfonyl) imide)F 4(0.04mmol) and the reaction time was 1 hour, the same procedure as in example 1 was repeated except that the yield was 69%.
Example 13
The reaction temperature was replaced with 60 ℃ and the other conditions were the same as in example 1, giving a yield of 86%.
Substrate development examples
Based on the determination of the optimal conditions (example 1), the reaction conditions of example 1 are taken as templates, the adaptability of different types of substrates to the reaction system is studied, and a series of indole-fused octa-lactam compounds are prepared, and the reaction formula and the results are as follows:
Figure BDA0002334465740000081
EXAMPLE 14 Synthesis of Compound III-2
Figure BDA0002334465740000091
The yield was 72%. White solid (mp 175-.1H NMR(500MHz,CDCl3)δ8.05(d,J＝8.5Hz,1H),7.30–7.26(m,1H),7.14–7.07(m,5H),6.86(d,J＝8.0Hz,1H),5.47(s,1H),4.09–3.97(m,1H),3.83–3.73(m,1H),3.54–3.41(m,1H),3.35(s,3H),3.30–3.20(m,1H),3.17(s,3H),2.34(s,3H),2.06–2.02(m,2H)；13C NMR(100MHz,CDCl3)δ174.2,137.8,135.9,132.7,129.6,128.8,128.4,124.9,123.6,120.2,117.5,114.5,53.4,42.7,42.4,41.6,28.5,21.1,20.0；IR(neat):2930,1682(s),1454,1361,1265,1162,962,768,619,541；HRESIMS Calcd for[C22H24N2NaO5S2]+(M+Na+)483.1019,found 483.1011.。
EXAMPLE 15 Synthesis of III-3 of the Compound
Figure BDA0002334465740000092
The yield was 81%. White solid (mp 245-.1H NMR(500MHz,CDCl3)δ8.04(d,J＝8.5Hz,1H),7.31–7.24(m,1H),7.13–7.07(m,3H),6.88–6.82(m,3H),5.45(s,1H),4.08–3.98(m,1H),3.84–3.73(m,4H),3.51–3.39(m,1H),3.34(s,3H),3.31–3.21(m,1H),3.16(s,3H),2.07–1.98(m,2H)；13C NMR(125MHz,CDCl3)δ174.3,159.2,136.0,134.2,129.7,128.8,127.7,124.9,123.7,120.3,117.8,114.5,114.3,55.2,53.0,42.7,42.5,41.6,28.5,20.0；IR(neat):2932,1685(s),1512,1454,1360,1253,1161,961,768,541；HRESIMS Calcd for[C22H24N2NaO6S2]+(M+Na+)499.0968,found 499.0971.。
EXAMPLE 16 Synthesis of Compound III-4
Figure BDA0002334465740000101
The yield is 89%; white solid (mp 218-.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.4Hz,1H),7.31–7.26(m,1H),7.19(s,2H),7.09(t,J＝7.6Hz,1H),7.05–6.98(m,2H),6.82(d,J＝8.0Hz,1H),5.46(s,1H),4.13–3.98(m,1H),3.85–3.72(m,1H),3.49–3.27(m,5H),3.18(s,3H),2.14–1.93(m,2H)；13C NMR(100MHz,CDCl3)δ173.9,162.2(d,J＝246.3Hz),135.9,134.1,131.9,130.4(d,J＝8.1Hz),128.4,125.0,123.7,120.0,117.4,115.8(d,J＝21.6Hz),114.5,52.7,42.8,42.5,41.7,28.4,20.0。
EXAMPLE 17 Synthesis of III-5 of the Compound
Figure BDA0002334465740000102
The yield is 94%; a yellow oily liquid.1H NMR(500MHz,CDCl3)δ8.05(d,J＝8.5Hz,1H),7.32–7.27(m,3H),7.19–7.13(m,2H),7.12–7.08(m,1H),6.82(d,J＝7.5Hz,1H),5.45(s,1H),4.09–3.97(m,1H),3.83–3.73(m,1H),3.45–3.30(m,5H),3.18(s,3H),2.13–1.94(m,2H)；13C NMR(100MHz,CDCl3)δ173.7,135.9,134.7,134.2,133.9,130.1,129.0,128.3,125.1,123.7,120.0,117.1,114.5,52.8,42.9,42.5,41.7,28.3,19.9。
EXAMPLE 18 Synthesis of III-6 of the Compound
Figure BDA0002334465740000111
The yield is 86%; white solid (mp 211-212 ℃).1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.4Hz,1H),7.46(d,J＝8.0Hz,2H),7.35–7.22(m,1H),7.12–7.02(m,3H),6.82(d,J＝7.6Hz,1H),5.43(s,1H),4.11–3.95(m,1H),3.85–3.71(m,1H),3.48–3.26(m,5H),3.18(s,3H),2.15–1.92(m,2H)；13C NMR(100MHz,CDCl3)δ173.5,135.9,135.2,134.3,132.0,130.4,128.3,125.1,123.8,122.1,120.0,117.0,114.5,52.8,42.9,42.5,41.7,28.4,20.1。
Synthesis of III-7 of the Compound of example 19
Figure BDA0002334465740000112
The yield is 97%; brown oily liquid.1H NMR(400MHz,CDCl3)δ10.00(s,1H),8.06(d,J＝8.4Hz,1H),7.86(d,J＝8.4Hz,2H),7.41(d,J＝7.2Hz,2H),7.31–7.24(m,1H),7.07(t,J＝8.0Hz,1H),6.78(d,J＝8.0Hz,1H),5.54(s,1H),4.17–4.01(m,1H),3.85–3.71(m,1H),3.59–3.26(m,5H),3.21(s,3H),2.19–1.92(m,2H)；13C NMR(100MHz,CDCl3)δ191.5,173.2,143.1,135.9,135.8,134.3,130.0,129.7,128.1,125.1,123.7,119.7,116.9,114.6,53.1,42.9,42.6,41.7,28.3,20.0。
EXAMPLE 20 Synthesis of III-8 Compound
Figure BDA0002334465740000121
The yield is 85%; yellow solid (mp 178-.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.8Hz,1H),8.00(d,J＝8.8Hz,2H),7.33–7.25(m,3H),7.06(t,J＝7.6Hz,1H),6.78(d,J＝8.0Hz,1H),5.53(s,1H),4.14–3.97(m,1H),3.90(s,3H),3.85–3.70(m,1H),3.50–3.25(m,5H),3.19(s,3H),2.16–1.92(m,2H)；13C NMR(100MHz,CDCl3)δ173.4,166.4,141.2,135.9,134.3,130.0,129.8,128.9,128.3,125.1,123.7,119.9,117.0,114.5,53.3,52.2,42.9,42.5,41.7,28.4,19.9
Synthesis of III-9 of the Compound of example 21
Figure BDA0002334465740000122
The yield is 99 percent; a colorless liquid.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,2H),7.37–7.27(m,3H),7.09(t,J＝7.6Hz,1H),6.74(d,J＝8.0Hz,1H),5.50(s,1H),4.19–3.99(m,1H),3.86–3.69(m,1H),3.63–3.47(m,1H),3.34(s,3H),3.29–3.02(m 4H),2.19–1.87(m,2H)；13C NMR(125MHz,CDCl3)δ173.1,141.9,136.0,134.5,132.5,129.9,127.9,125.2,123.9,119.6,118.3,116.6,114.6,112.0,53.0,43.1,42.7,41.8,28.3,20.1。
Synthesis of III-10 of the Compound of example 22
Figure BDA0002334465740000131
The yield was 89%. White solid (mp 143-144 ℃).1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.4Hz,1H),7.92(d,J＝8.4Hz,2H),7.35–7.24(m,3H),7.07(t,J＝7.6Hz,1H),6.79(d,J＝7.6Hz,1H),5.53(s,1H),4.17–3.98(m,1H),3.85–3.71(m,1H),3.51–3.26(m,5H),3.20(s,3H),2.58(s,3H),2.17–1.92(m,2H)；13C NMR(100MHz,CDCl3)δ197.3,173.4,141.5,136.7,135.9,134.3,129.1,128.8,128.2,125.1,123.8,119.8,117.0,114.6,53.2,42.9,42.6,41.7,28.4,26.5,20.0。
Synthesis of III-11 of the Compound of example 23
Figure BDA0002334465740000132
The yield is 99 percent; yellow solid (mp 175-.1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.8Hz,2H),8.05(d,J＝8.4Hz,1H),7.42(d,J＝7.6Hz,2H),7.31–7.24(m,1H),7.08(t,J＝7.6Hz,1H),6.75(d,J＝8.0Hz,1H),5.55(s,1H),4.21–4.03(m,1H),3.85–3.71(m,1H),3.68–3.50(m,1H),3.35(s,3H),3.29–3.04(m,4H),2.21–1.88(m,2H)；13CNMR(100MHz,CDCl3)δ173.0,147.5,143.9,136.0,134.6,130.1,127.8,125.3,123.9,119.6,116.6,114.7,52.6,43.1,42.7,41.9,28.3,20.0。
EXAMPLE 24 Synthesis of Compound III-12
Figure BDA0002334465740000141
The yield is 72%; a colorless liquid.1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.4Hz,1H),7.34–7.23(m,1H),7.20(t,J＝7.6Hz,1H),7.14–7.04(m,3H),7.02–6.91(m,1H),6.86(d,J＝8.0Hz,1H),5.46(s,1H),4.14–3.98(m,1H),3.84–3.70(m,1H),3.55–3.23(m,5H),3.17(s,3H),2.31(s,3H),2.12–1.94(m,2H)；13C NMR(100MHz,CDCl3)δ174.1,138.6,135.9,135.8,134.2,129.2,128.8,128.6,125.7,124.9,123.6,120.2,117.5,114.4,53.6,42.8,42.4,41.6,28.5,21.4,20.0。
EXAMPLE 25 Synthesis of Compound III-13
Figure BDA0002334465740000142
The yield is 76%; brown oily liquid.1H NMR(500MHz,CDCl3)δ8.04(d,J＝8.5Hz,1H),7.30–7.22(m,2H),7.09(t,J＝7.0Hz,1H),6.89(d,J＝7.5Hz,1H),6.86–6.83(m,1H),6.83–6.69(m,2H),5.47(s,1H),4.11–3.98(m,1H),3.82–3.70(m,4H),3.53–3.39(m,1H),3.35(s,3H),3.31–3.20(m,1H),3.16(s,3H),2.11–1.92(m,2H)；13C NMR(125MHz,CDCl3)δ173.9,159.9,137.4,135.9,134.3,129.8,128.8,125.0,123.7,121.0,120.2,117.4,115.0,114.5,112.9,55.2,53.6,42.8,42.5,41.6,28.5,20.0
EXAMPLE 26 Synthesis of Compounds III-14
Figure BDA0002334465740000151
The yield is 97%; a colorless oily liquid.1H NMR(400MHz,DMSO)δ7.94(d,J＝8.4Hz,1H),7.40–7.34(m,1H),7.24(t,J＝7.6Hz,1H),7.15–7.04(m,4H),6.82(d,J＝7.6Hz,1H),5.92(s,1H),4.11–3.97(m,1H),3.85–3.69(m,1H),3.68–3.55(m,1H),3.49(s,3H),3.39–3.26(m,4H),2.05(s,1H),1.75(s,1H)；13C NMR(125MHz,DMSO)δ173.7,162.4(d,J＝241.6Hz),141.5,136.0,130.4(d,J＝8.4Hz),128.4,126.1,124.6,123.3,120.3,117.8,116.8(d,J＝22.2Hz),114.5,114.4(d,J＝20.6Hz),51.4,43.1,42.5,42.0,27.8,20.5。
EXAMPLE 27 Synthesis of Compounds III-15
Figure BDA0002334465740000152
The yield is 73%; a colorless oily liquid.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.8Hz,1H),7.32–7.24(m,3H),7.21(s,1H),7.12–7.07(m,2H),6.84(d,J＝8.0Hz,1H),5.43(s,1H),4.15–4.00(m,1H),3.83–3.69(m,1H),3.52–3.26(m,5H),3.18(s,3H),2.17–1.90(m,2H)；13C NMR(100MHz,CDCl3)δ173.4,138.4,136.0,134.7,134.3,130.0,128.9,128.3,127.1,125.1,123.8,119.9,117.1,114.6,53.0,43.0,42.6,41.7,28.4,20.0。
EXAMPLE 28 Synthesis of Compound III-16
Figure BDA0002334465740000161
The yield is 73%; a colorless oily liquid.1H NMR(500MHz,CDCl3)δ8.05(d,J＝8.5Hz,1H),7.45(d,J＝7.5Hz,1H),7.38(s,1H),7.29(t,J＝7.5Hz,1H),7.21(t,J＝7.5Hz,1H),7.15–7.08(m,2H),6.84(d,J＝7.5Hz,1H),5.42(s,1H),4.14–4.01(m 1H),3.84–3.69(m,1H),3.56–3.23(m,5H),3.18(s,3H),2.17–1.91(m,2H)；13C NMR(100MHz,CDCl3)δ173.4,138.6,136.0,134.3,131.8,131.1,130.3,128.2,127.6,125.1,123.8,122.8,119.9,117.0,114.6,52.8,42.9,42.5,41.7,28.4,20.1。
EXAMPLE 29 Synthesis of Compounds III-17
Figure BDA0002334465740000162
The yield is 92%; white solid (mp 225-.1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.8Hz,1H),7.36–7.30(m,3H),7.22(s,2H),7.11–7.08(m,1H),6.62(s,1H),5.47(s,1H),4.10–3.93(m,1H),3.85–3.68(m,1H),3.52–3.39(m,1H),3.35(s,3H),3.29–3.19(m,1H),3.13(s,3H),2.24(s,3H),2.08–1.96(m,2H)；13C NMR(100MHz,CDCl3)δ174.1,135.9,134.2,133.5,129.0,128.8,128.5,128.0,126.4,119.9,117.4,114.2,53.6,42.8,42.4,41.3,28.5,21.2,20.0。
EXAMPLE 30 Synthesis of Compounds III-18
Figure BDA0002334465740000171
The yield is 68 percent; a yellow oily liquid.1H NMR(400MHz,CDCl3)δ7.98(d,J＝8.8Hz,1H),7.38–7.34(m,3H),7.25–7.12(m,3H),6.79(d,J＝2.0Hz,1H),5.45(s,1H),4.09–3.94(m,1H),3.83–3.69(m,1H),3.52–3.38(m,1H),3.34(s,3H),3.30–3.24(m,1H),3.19(s,3H),2.01–1.97(m,2H)；13C NMR(125MHz,CDCl3)δ173.6,135.7,135.4,134.3,129.9,129.5,129.0,128.5,128.3,125.2,119.7,116.8,115.6,53.5,42.8,42.5,41.9,28.5,20.2。
EXAMPLE 31 Synthesis of Compounds III-19
Figure BDA0002334465740000172
The yield is 71%; brown oily liquid.1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.8Hz,1H),7.39–7.34(m,4H),7.19(s,2H),6.94(d,J＝1.6Hz,1H),5.45(s,1H),4.09–3.94(m,1H),3.82–3.69(m,1H),3.50–3.37(m,1H),3.34(s,3H),3.30–3.22(m,1H),3.19(s,3H),2.10–1.98(m,2H)；13C NMR(100MHz,CDCl3)δ173.6,135.6,135.3,134.6,130.4,129.0,128.5,128.3,127.9,122.7,117.1,116.6,116.0,53.4,42.7,42.4,42.0,28.5,20.1。
EXAMPLE 32 Synthesis of Compound III-20
Figure BDA0002334465740000173
The yield is 95%; white solid (mp 238-.1H NMR(500MHz,CDCl3)δ7.86(s,1H),7.34–7.29(m,3H),7.21(s,2H)),6.90(d,J＝8.0Hz,1H),6.70(d,J＝8.0Hz,1H),5.47(s,1H),4.11–3.98(m,1H),3.83–3.70(m,1H),3.47–3.23(m,5H),3.15(s,3H),2.43(s,3H),2.09–1.94(m,2H)；13C NMR(125MHz,CDCl3)δ174.0,136.4,136.0,135.2,133.6,128.8,128.7,127.9,126.5,125.2,119.8,117.6,114.7,53.6,42.8,42.5,41.4,28.5,21.8,20.1。
EXAMPLE 33 Synthesis of Compounds III-21
Figure BDA0002334465740000181
The yield is 76%; white solid (mp 236-.1H NMR(400MHz,CDCl3)δ7.81(d,J＝10.4Hz,1H),7.41–7.29(m,3H),7.21(s,2H),6.86–6.81(m,1H),6.76–6.70(m,1H),5.48(s,1H),4.12–3.97(m,1H),3.85–3.73(m,1H),3.51–3.38(m,1H),3.35(s,3H),3.32–3.24(m,1H),3.20(s,3H),2.09–1.99(m,2H)；13C NMR(100MHz,DMSO)δ173.9,159.9(d,J＝237.1Hz),135.9(d,J＝11.8Hz),129.8,128.6,127.6,125.1,121.5(d,J＝9.3Hz),117.8,111.3(d,J＝23.6Hz),101.7(d,J＝29.0Hz),51.7,43.1,42.4,42.2,27.8,20.2。
EXAMPLE 34 Synthesis of Compound III-22
Figure BDA0002334465740000182
The yield is 75%; white solid (mp 206-.1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.37–7.32(m,3H),7.19(s,2H),7.07–7.03(m,1H),6.73(d,J＝8.4Hz,1H),5.47(s,1H),4.11–3.97(m,1H),3.85–3.71(m,1H),3.50–3.38(m,1H),3.34(s,3H),3.31–3.26(m,1H),3.22(s,3H),2.12–1.96(m,2H)；13C NMR(125MHz,DMSO)δ173.9,136.3,129.8,129.2,128.7,127.7,123.5,121.8,117.8,114.4,51.7,43.2,42.5,27.8,20.4。
EXAMPLE 35 Synthesis of Compounds III-23
Figure BDA0002334465740000191
The yield is 74%; brown oily liquid (mp 224-.1H NMR(400MHz,CDCl3)δ7.40–7.33(m,3H),7.26–7.21(m,2H),6.93(s,1H),6.48(s,1H),5.36(s,1H),4.05–3.91(m,1H),3.77–3.65(m,1H),3.37(s,3H),3.26–3.10(m,2H),3.02(s,2H),2.62(s,3H),2.21(s,3H),2.18–2.10(m,1H),2.05–1.91(m,1H)；13C NMR(125MHz,CDCl3)δ173.7,138.6,136.7,135.8,135.0,133.0,130.4,129.0,128.3,128.1,127.8,122.0,117.8,53.7,43.1,42.5,39.8,28.4,22.5,21.6,21.0。
EXAMPLE 36 Synthesis of Compounds III-24
Figure BDA0002334465740000192
The yield is 96%; yellow solid (mp 101-.1H NMR(400MHz,CDCl3)δ8.27(d,J＝8.4Hz,1H),7.64(d,J＝8.4Hz,2H),7.30–7.23(m,6H),7.07–7.02(m,3H),6.77(d,J＝8.0Hz,1H),5.39(s,1H),4.09–3.94(m,1H),3.74–3.67(m,1H),3.39–3.18(m,5H),2.40(s,3H),2.07–1.83(m,2H)；13C NMR(100MHz,CDCl3)δ174.0,145.2,136.8,136.1,134.3,130.0,128.9,128.7,127.9,126.2,124.9,123.6,119.8,118.1,115.3,53.3,42.8,42.5,28.5,21.6,20.2。
EXAMPLE 37 Synthesis of Compounds III-25
Figure BDA0002334465740000201
The yield is 80%; brown solid (mp 227-.1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.4Hz,1H),7.59(s,4H),7.32–7.26(m,4H),7.07(t,J＝8.0Hz,1H),6.99(s,2H),6.78(d,J＝7.6Hz,1H),5.38(s,1H),4.10–3.97(m,1H),3.74–3.67(m,1H),3.45–3.15(m,5H),2.11–1.85(m,2H)；13C NMR(100MHz,CDCl3)δ173.8,137.6,136.7,135.9,134.2,132.8,129.3,129.1,128.8,128.6,127.9,127.6,125.2,124.1,120.0,119.2,115.4,53.3,42.7,42.5,28.5,20.2。
The embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.

Claims (8)

1. A method for preparing an indole-fused octamer lactam compound comprising the steps of: adding auxiliary agent NaBAr into the reactor in sequenceF 4Catalyst zinc triflate (Zn (OTf)2) Indolylalkynylalkylamide compound shown as formula I and N-oxide oxidant, then adding organic solvent, replacing the reactor with inert atmosphere, heating and stirring at 40-100 ℃ for reaction, and monitoring by TLCAfter the reaction is detected to be complete, concentrating the reaction solution to obtain a residue, and separating by silica gel column chromatography to obtain an indole-condensed octamer lactam compound shown in the formula III; the reaction formula is as follows:
Figure FDA0002334465730000011
wherein, in formula I and formula III, R1Represents one or more substituents on the attached phenyl ring, each R1The substituents are independently of one another selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl radical, C1-6Acyl, -CN, -NO2；
R2Represents substituted or unsubstituted C6-14An aryl group; wherein the "substituents" in this expression substituted or unsubstituted are selected from halogen, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl radical, C1-6Acyl, -CN, -NO2、-C(O)O C1-6Any one or more of alkyl;
PG1and PG2Represents a protecting group selected independently from any one of Ms (methylsulfonyl), Ts (p-toluenesulfonyl) and/or Bs (p-bromophenylsulfonyl);
the auxiliary agent NaBArF 4The structure is as follows:
Figure FDA0002334465730000012
the structure of the N-oxide oxidant is as follows:
Figure FDA0002334465730000021
wherein, the substituent R in the formula II represents 2-Br,2-Cl, 3,5-Cl2,2,6-Br2,2,6-Cl2Any one of them.
2. The process according to claim 1, wherein R in formula I and formula III1Represents one or more substitutions on the attached phenyl ringRadical, each R1The substituents are independently from each other selected from hydrogen, chlorine, bromine, methyl;
R2represents a substituted or unsubstituted phenyl group; wherein the "substituent" in this expression substituted or unsubstituted is selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy, aldehyde, -C (O) OMe, -CN, -NO2、-C(O)CH3Any one or more of them;
in the formula II, R preferably represents 2,6-Br2,2,6-Cl2Any one of them.
3. The process according to claim 2, wherein R in formula II represents 2,6-Cl2。
4. The process according to any one of claims 1 to 3, wherein the organic solvent is chosen from Dichloroethane (DCE).
5. The production method according to any one of claims 1 to 4, wherein the inert gas atmosphere is selected from a nitrogen gas atmosphere or an argon gas atmosphere; preferably, the inert atmosphere is selected from a nitrogen atmosphere.
6. The method of any one of claims 1 to 5, wherein the reaction temperature is preferably 60 to 80 ℃, most preferably 80 ℃.
7. The method according to any one of claims 1 to 6, wherein the reaction time of the heating and stirring reaction is 10min to 12 hours, and preferably the reaction time of the heating and stirring reaction is 0.5 hour.
8. The process according to any one of claims 1 to 7, wherein the indolylcarbonylamide compound represented by formula I, zinc trifluoromethanesulfonate (Zn (OTf))2) Auxiliary agent NaBArF 4The feeding molar ratio of the N-oxide oxidant to the N-oxide oxidant is 1 (0.05-0.2) to (0.1-0.4) to (1-3); preferably, the indolyalkynoyl of formula IAmine compound, catalyst zinc trifluoromethanesulfonate (Zn (OTf)2) Auxiliary agent NaBArF 4And the feeding molar ratio of the N-oxide oxidant is 1 (0.1) to (0.2) to (2).
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