CN111592544A - Indoline aza eight-membered ring derivative and synthesis method thereof - Google Patents
Indoline aza eight-membered ring derivative and synthesis method thereof Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 51
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 32
- -1 6-chlorophenyl Chemical group 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 26
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 18
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 11
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 9
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- FLPJQQDDZSHBDC-MKYGIPPKSA-N chembl326531 Chemical compound C1C\C=C/CCCCN2CC[C@H]3C(C4=C5N=C6C=CC=CC6=C5C=CN4)=C[C@]1(O)[C@@H]1N4CCCC\C=C/[C@H]4C[C@@]13C2 FLPJQQDDZSHBDC-MKYGIPPKSA-N 0.000 claims description 2
- 229930183047 manzamine Natural products 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 230000004071 biological effect Effects 0.000 abstract description 4
- 229930014626 natural product Natural products 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 150000002576 ketones Chemical class 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 230000003595 spectral effect Effects 0.000 description 14
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 241001480486 Haliclona sp. Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910010293 ceramic material Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 150000002476 indolines Chemical class 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- FUCSLKWLLSEMDQ-MKYGIPPKSA-N manzamine A Chemical compound C1C\C=C/CCCCN2CC[C@H]3C(C=4C=5NC6=CC=CC=C6C=5C=CN=4)=C[C@]1(O)[C@@H]1N4CCCC\C=C/[C@H]4C[C@@]13C2 FUCSLKWLLSEMDQ-MKYGIPPKSA-N 0.000 description 1
- FUCSLKWLLSEMDQ-UHFFFAOYSA-N manzamine A hydrochloride Natural products C1CC=CCCCCN2CCC3C(C=4C=5NC6=CC=CC=C6C=5C=CN=4)=CC1(O)C1N4CCCCC=CC4CC13C2 FUCSLKWLLSEMDQ-UHFFFAOYSA-N 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses an indoline aza eight-membered ring derivative shown in formula (I) and a synthesis method thereof. The preparation method has the advantages of simple and easily obtained raw materials, good universality, high atom economy, simple post-treatment, good yield, environmental friendliness and the like. The indoline aza eight-membered ring framework disclosed by the invention is an important structural unit in a plurality of natural product molecules, and most of the compounds have stronger biological activity and have great research value in the aspect of drug synthesis.
Description
Technical Field
The invention belongs to the technical field of organic compounds and synthesis, and relates to a synthesis method of zinc-catalyzed and alkali-promoted indolino-aza-eight-membered ring derivatives.
Background
The indolino aza eight membered ring skeleton is widely present in natural product molecules. For example, the indoline alkaloid, Manzamine a, was isolated from the sponge Haliclona sp. by Higa et al, 1986, and a number of reports have been made on its synthesis and properties. For example: document (1) Winkler, j.d.; axton, j.m.j.am.chem.soc.1998,120,6425.(2) hummphrey, j.m.; liao, y.; ali, a.; rein, t.; wong, Y. -L.; chen, h. -j.; courtney, a.k.; martin, s.f.j.am.chem.soc.2002,124,8584.(3) Bonazzi, s.; cheng, b.; wzorek, j.s.; the research of Evans, D.A.J.Am.chem.Soc.2013,135,9338 shows that the compounds have wide biological activity, such as insecticidal activity, antibacterial activity, anti-inflammatory activity, antiviral activity, antimalarial activity and the like. However, the structure of the compound is complex, particularly the construction difficulty of the indoline nitrogen heterocyclic eight-membered ring as the core unit is very large, and the reported method generally needs multi-step synthesis and is relatively complex, so that the research on the indoline compound containing the structure is severely limited. Therefore, a method for constructing the indoline and nitrogen heterocyclic eight-membered ring derivative with more economy and high efficiency and simple reaction conditions is developed, the activity of the compound is further researched, and the method has great significance for new drug synthesis.
Disclosure of Invention
The invention aims to provide an indoline aza eight-membered ring derivative and a synthesis method thereof, wherein the method is a synthesis method which is zinc-catalyzed, subsequent alkali-promoted, low in cost and environment-friendly. The indoline aza eight-membered ring derivative provided by the invention is a main structural unit in a plurality of natural products, and most derivatives have stronger biological activity and have great research value in the aspect of drug synthesis.
The structure of the indoline aza eight-membered ring derivative provided by the invention is shown as the formula (I):
wherein the content of the first and second substances,
R1、R2respectively aryl, alkyl substituted aryl, alkoxy substituted aryl and halogen substituted aryl;
R3、R4aryl, alkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, naphthyl, thienyl, alkyl;
preferably, the first and second electrodes are formed of a metal,
R1is phenyl, C1-C10 alkyl substituted phenyl, bromine substituted phenyl;
R2is phenyl, C1-C10 alkoxy substituted phenyl, chloro substituted phenyl;
R3is phenyl, C1-C10 alkoxy substituted phenyl, fluoro substituted phenyl, naphthyl, C1-C10 alkyl;
R4is phenyl, C1-C10 alkoxy substituted phenyl, chloro substituted phenyl, cyano substituted phenyl, thienyl, C1-C10 alkyl.
It is further preferred that the first and second liquid crystal compositions,
R1is phenyl, 4-methylphenyl, 4-bromophenyl;
R2is phenyl, 4-methoxyphenyl, 6-chlorophenyl;
R3is phenyl, 3,4, 5-trimethoxyphenyl, p-fluorophenyl, 1-naphthyl or tert-butyl;
R4is phenyl, p-methoxyphenyl, m-chlorophenyl, p-cyanophenyl, 1-thienyl or n-butyl.
The invention also provides a synthesis method of the indoline and aza eight-membered ring derivative shown in the formula (I), wherein in the first step, the raw material indole compound reacts in a solvent under the action of zinc iodide, and in the second step, the alkynone compound, the solvent and alkali are added into the reaction system for reaction to synthesize the indoline and aza eight-membered ring derivative shown in the formula (I); the reaction process is shown as the formula (II):
wherein the content of the first and second substances,
R1、R2respectively aryl, alkyl substituted aryl, alkoxy substituted aryl and halogen substituted arylA group;
R3、R4aryl, alkyl-substituted aryl, alkoxy-substituted aryl, halogen-substituted aryl, cyano-substituted aryl, naphthyl, thienyl, alkyl;
preferably, the first and second electrodes are formed of a metal,
R1is phenyl, C1-C10 alkyl substituted phenyl, bromine substituted phenyl;
R2is phenyl, C1-C10 alkoxy substituted phenyl, chloro substituted phenyl;
R3is phenyl, C1-C10 alkoxy substituted phenyl, fluoro substituted phenyl, naphthyl, C1-C10 alkyl;
R4is phenyl, C1-C10 alkoxy substituted phenyl, chloro substituted phenyl, cyano substituted phenyl, thienyl, C1-C10 alkyl.
It is further preferred that the first and second liquid crystal compositions,
R1is phenyl, 4-methylphenyl, 4-bromophenyl;
R2is phenyl, 4-methoxyphenyl, 6-chlorophenyl;
R3is phenyl, 3,4, 5-trimethoxyphenyl, p-fluorophenyl, 1-naphthyl or tert-butyl;
R4is phenyl, p-methoxyphenyl, m-chlorophenyl, p-cyanophenyl, 1-thienyl or n-butyl.
Wherein the alkynone compound is alkynone with an electron-withdrawing group connected on a benzene ring, alkynone with an electron-donating group connected on a benzene ring, naphthyl alkynone, heteroaryl alkynone and alkyl alkynone.
Wherein, the solvent in the first step is one or more of toluene, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloroethane and the like; preferably, it is toluene.
Wherein the reaction temperature in the first step is room temperature to 80 ℃; preferably, it is room temperature, 50 deg.C, 80 deg.C; further preferably 80 ℃.
Wherein the reaction time in the first step is 2-24 hours; preferably, it is 2 hours.
Wherein, the solvent in the second step is one or more of acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, toluene and the like; preferably, it is dimethyl sulfoxide.
Wherein the base is a catalyst, and comprises NaOH and KOtBu、K2CO3、Cs2CO3One or more of DBU, etc.; preferably, it is Cs2CO3。
Wherein the reaction temperature in the second step is 50-110 ℃; preferably, 50 ℃, 80 ℃, 110 ℃; further preferably 80 ℃.
Wherein the reaction time in the second step is 3-19 hours; preferably, it is 6 hours.
Wherein the mol ratio of the indole compound, the zinc iodide, the alkynone compound and the alkali is 1: 0.05: 1: 1-3.
In a specific embodiment, the synthesis method comprises the steps of reacting a raw material indole compound in toluene under the action of zinc iodide in the air, continuing to add an alkynone compound, a solvent and a base into a reaction system after the raw material is consumed, and synthesizing to obtain the indoline and aza-eight-membered ring derivative shown in the formula (I); the reaction process is shown as the formula (II'):
wherein R is1、R2、R3、R4Is as defined in formula (II).
The invention relates to a method for preparing a high-temperature-resistant ceramic material. The invention adopts a one-pot method strategy, combines the dearomatization reaction with the carbon-carbon bond cutting reaction without separation, so that the post-treatment of the reaction is simple and convenient, and a good choice is provided for the construction of complex molecular frameworks which are difficult to complete by the traditional method.
The invention also provides application of the indoline aza eight-membered ring derivative in preparation of Manzamine A.
The invention has the beneficial effects that: the synthesis method has the advantages of simple and easily obtained raw materials, good universality, high atom economy, simple post-treatment, good yield (51-83%), environmental friendliness and the like. The indoline nitrogen-heterocyclic eight-membered ring framework is an important structural unit in a plurality of natural product molecules, and most of the compounds have stronger biological activity and have great research value in the aspect of drug synthesis.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, implementation methods and the like for carrying out the present invention are general knowledge and well-known attempts in the art, except for those specifically mentioned below, and the present invention is not particularly limited thereto.
Example 1: synthesis of IA
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 6 hours to give the desired product of formula (IA) as a yellow solid in 77% isolated yield. mp 246-248 ℃.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.67(s,1H),7.50(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.37-7.19(m,7H),7.16-7.03(m,7H),6.98(d,J＝7.6Hz,1H),6.87-6.79(m,1H),5.90-5.75(m,1H),3.82(dd,J1＝15.2Hz,J2＝15.6Hz,1H),3.46(dd,J1＝15.2Hz,J2＝15.2Hz,1H).13C NMR(100MHz,CDCl3)185.40,181.71,153.44,139.36,132.03,130.21,129.20,124.91,124.75,124.33,123.59,123.16,122.17,122.03,121.33,121.21,120.94,120.80,118.23,116.04,115.46,113.33,110.34,106.27,104.81,102.26,57.49,28.23.
high resolution mass spectral data: HRMS (ESI) calcd for C32H23N2O2[M+H]+:467.1754；found467.1755.
Example 2: synthesis of IB
Under air, 3- (2- (1H-indol-1-yl) -5-methylphenyl) -3-oxopropanenitrile (0.2mmol), ZnI2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for a further 6 h to give the desired product of formula (IB) as a yellow solid in 83% isolated yield. mp 234-.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.70(s,1H),7.38(d,J＝8.4Hz,1H),7.30-7.02(m,14H),6.92(d,J＝8.0Hz,1H),6.84-6.76(m,1H),5.79(t,J＝10.4Hz,1H),3.86-70(m,1H),3.43(dd,J1＝15.6Hz,J2＝15.6Hz,1H),2.32(s,1H).13C NMR(100MHz,CDCl3)192.50,188.76,160.32,146.63,137.31,136.44,136.27,132.74,132.71,131.83,131.10,130.60,130.09,129.08,128.30,128.18,127.90,127.79,125.15,122.47,119.98,117.37,113.29,111.89,109.04,64.47,35.18,20.34.
high resolution mass spectral data: HRMS (ESI) calcd for C33H25N2O2[M+H]+:481.1911；found481.1915.
Example 3: synthesis of IC
Under air, 3- (5-bromo-2- (1H-indol-1-yl) phenyl) -3-oxopropanenitrile (0.2mmol), ZnI2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for a further 6 hours to give the desired product of formula (IC) as a yellow solid isolated in 66% yield. mp 236-238 ℃.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.70(s,1H),7.54(s,1H),7.46-7.34(m,2H),7.32-7.04(m,12H),6.94(d,J＝8.0Hz,1H),6.88-6.80(m,1H),5.79(t,J＝10.4Hz,1H),3.82(dd,J1＝15.6Hz,J2＝16.0Hz，1H)，3.46(dd，J1＝15.2Hz，J2＝15.6Hz，1H).13C NMR(100MHz，CDCl3)190.86188.63,160.31,145.85,138.25,136.88,135.80,134.66,132.98,132.89,132.12,130.40,129.24,129.08,128.37,128.34,127.99,127.87,125.35,123.90,120.80,117.18,115.13,113.11,111.48,109.27,64.51,35.22.
high resolution mass spectral data: HRMS (ESI) calcd for C32H22BrN2O2[M+H]+:545.0859；found545.0857.
Example 4: synthesis of ID
Under air, 3- (2- (4-methoxy-1H-indol-1-yl) phenyl) -3-oxopropanenitrile (0.2mmol), ZnI2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 6 hours to give the desired product of formula (ID) as a yellow solid in 61% isolated yield. mp 250-252 ℃.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.63(s,1H),7.49(d,J＝8.4Hz,1H),7.40(d,J＝7.6Hz,1H),7.36-7.24(m,4H),7.24-7.17(m,2H),7.16-7.97(m,7H),6.63(d,J＝8.4Hz,1H),6.42(d,J＝8.4Hz,1H),5.85(d,J＝10.0Hz,1H),3.87(s,1H),3.67(dd,J1＝15.2Hz,J2＝16.0Hz,1H),3.51(dd,J1＝15.6Hz,J2＝16.0Hz,1H).13C NMR(100MHz,CDCl3)192.35,188.74,160.25,156.77,147.73,139.24,137.20,136.24,131.89,131.68,131.24,130.48,130.12,129.15,129.03,128.33,128.19,127.91,122.92,122.50,117.30,115.78,113.33,111.90,103.17,103.05,64.90,55.29,32.20.
high resolution mass spectral data: HRMS (ESI) calcd for C25H18NaO4[M+H]+:367.1329；found367.1335.
Example 5: synthesis of IE
3- (2- (5-chloro-1H-indol-1-yl) phenyl) -3-oxopropanenitrile (0.2mmol), ZnI2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 6 hours to give the desired product of formula (IE) as a yellow solid in 71% isolated yield. mp 235-.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.68(s,1H),7.48-7.38(m,2H),7.37-7.24(m,4H),7.23-7.16(m,3H),7.14-6.98(m,7H),6.86(d,J＝8.0Hz,1H),5.82(t,J＝10.0Hz,1H),3.79(dd,J1＝14.8Hz,J2＝15.2Hz,1H),3.43(dd,J1＝16.0Hz,J2＝15.6Hz,1H).13C NMR(100MHz,CDCl3)192.16,188.87,160.68,145.02,138.66,137.06,136.08,131.99,131.87,131.38,131.06,130.65,130.28,129.01,128.34,128.24,127.94,127.59,125.35,124.67,123.38,122.11,117.21,113.16,111.29,110.02,64.65,34.91.
high resolution mass spectral data: HRMS (ESI) calcd for C32H22ClN2O2[M+H]+:501.1364；found501.1365.
Example 6: synthesis of IF
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by the addition of acetylenic ketone(s) (II) ((III))0.2mmol)，Cs2CO3(0.4mmol) and DMSO (2.0mL) were allowed to react at 80 ℃ for 10 hours to give the desired product of formula (IF) as a yellow solid in 66% isolated yield. mp 184 and 186 ℃.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.55(s,1H),7.50(d,J＝8.4Hz,1H),7.42(d,J＝7.6Hz,1H),7.39-7.32(m,1H),7.23-7.06(m,8H),6.97(d,J＝8.4Hz,1H),6.86-6.78(m,1H),6.54(s,1H),5.95-5.80(m,1H),3.90-3.80(m,1H),3.80(s,3H),3.78(s,6H),3.36(dd,J1＝15.2Hz,J2＝15.2Hz,1H).13C NMR(100MHz,CDCl3)190.72,189.13,161.06,153.00,146.34,141.41,139.23,137.18,131.87,131.61,130.99,130.76,130.35,128.90,128.36,127.89,125.21,123.12,122.52,120.40,117.22,113.11,111.06,109.40,105.57,64.76,60.81,55.97,35.19.
high resolution mass spectral data: HRMS (ESI) calcd for C35H29N2O5[M+H]+:557.2071；found557.2070.
Example 7: synthesis of IG
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 10 hours to give the desired product of formula (IG) as a yellow solid isolated in 51% yield. mp 238-.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.70(s,1H),7.51(d,J＝8.4Hz,1H),7.44-7.30(m,4H),7.28-7.22(m,1H),7.21-7.03(m,7H),7.01-6.80(m,4H),5.82(t,J＝10.4Hz,1H),3.82(dd,J1＝15.6Hz,J2＝15.6Hz,1H),3.45(dd,J1＝15.6Hz,J2＝15.2Hz,1H).13C NMR(100MHz,CDCl3)192.52,187.31,164.89(J＝127.2Hz),160.16,146.30,139.06,137.06,132.38(J＝3.3Hz),131.84,130.17(J＝105.3Hz),130.64,130.59,130.55,130.43,129.01,128.40,127.84,125.25,123.07,122.46,120.41,117.26,115.69,115.47,112.54(J＝51.7Hz),109.33,64.51,35.28.
high resolution mass spectral data: HRMS (ESI) calcd for C32H22FN2O2[M+H]+:485.1660；found485.1657.
Example 8: synthesis of IH
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for a further 10 h to give the desired product formula (IH) as a yellow solid isolated in 58% yield. mp 184 and 186 ℃.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.54(s,1H),7.78-7.66(m,2H),7.61-7.34(m,6H),7.25(d,J＝7.6Hz,1H),7.19-7.05(m,3H),7.01-6.74(m,6H),6.58(d,J＝7.6Hz,1H),5.84(t,J＝10.0Hz,1H),3.73(dd,J1＝15.2Hz,J2＝15.6Hz,1H),3.45(dd,J1＝15.6Hz,J2＝15.2Hz,1H).13C NMR(100MHz,CDCl3)192.21,190.61,159.69,146.48,138.56,137.41,133.95,133.14,131.71,131.20,130.98,130.70,129.37,129.27,128.98,128.46,128.02,127.86,126.89,126.57,125.96,125.24,124.64,124.54,123.00,122.80,120.34,117.01,115.59,111.64,108.82,63.96,35.26.
high resolution mass spectral data: HRMS (ESI) calcd for C36H25N2O2[M+H]+:517.1911；found517.1914.
Example 9: synthesis of II
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 6 hours to obtain the target product of formula (II) as a yellow solid in 53% isolated yield. mp 250-252 ℃.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)18.16(s,1H),7.59-7.52(m,2H),7.48-7.37(m,4H),7.33(d,J＝7.6Hz,1H),7.28-7.23(m,1H),7.20(d,J＝7.2Hz,1H),7.12-6.99(m,2H),6.94(d,J＝8.0Hz,1H),6.84-6.77(m,1H),5.67-5.58(m,1H),3.74(dd,J1＝15.2Hz,J2＝15.6Hz,1H),3.29(dd,J1＝15.2Hz,J2＝15.6Hz,1H),0,92(s,9H).13C NMR(100MHz,CDCl3)204.22,189.21,160.08,146.19,139.46,137.97,131.38,131.12,130.95,130.05,129.46,129.37,129.01,127.83,125.25,123.08,121.91,120.38,117.42,112.20,111.69,110.18,65.20,42.77,34.88,27.14.
high resolution mass spectral data: HRMS (ESI) calcd for C30H27N2O2[M+H]+:447.2067；found447.2068.
Example 10: synthesis of IJ
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 10 hours to obtain the target product of formula (IJ) as a yellow solid in isolated yield of 63%. mp 234-.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.70(s,1H),7.50(d,J＝8.4Hz,1H),7.41-7.28(m,5H),7.27-7.18(m,3H),7.17-7.03(m,4H),6.97(d,J＝8.0Hz,1H),6.86-6.78(m,1H),6.59(d,J＝8.4Hz,1H),5.82(t,J＝10.0Hz,1H),3.81(dd,J1＝15.2Hz,J2＝16.0Hz,1H),3.66(s,3H),3.44(dd,J1＝15.2Hz,J2＝15.6Hz,1H).13C NMR(100MHz,CDCl3)192.21,188.73,161,24,159.96,146.39,139.19,136.22,131.99,131.67,131.38,130.68,130.41,129.60,129.27,128.33,127.95,127.77,125.21,122.95,122.40,120.25,117.86,113.64,113.11,109.81,109.31,64.62,55.10,35.29.
high resolution mass spectral data: HRMS (ESI) calcd for C33H25N2O3[M+H]+:497.1860；found497.1859.
Example 11: IK Synthesis
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for a further 6 hours to give the desired product of formula (IK) as a yellow solid isolated in 80% yield. mp 230-.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.61(s,1H),7.51(d,J＝8.0Hz,1H),7.45-7.30(m,3H),7.27-7.20(m,5H),7.15-6.93(m,7H),6.88-6.78(m,1H),5.85-5.75(m,1H),3.80(dd,J1＝15.2Hz,J2＝15.6Hz,1H),3.46(dd,J1＝15.2Hz,J2＝15.6Hz,1H).13C NMR(100MHz,CDCl3)192.64,188.64,158.79,146.30,139.06,138.94,136.08,134.24,132.04,131.90,131.19,130.59,130.04,129.45,129.04,128.92,128.48,127.87,127.20,125.27,123.19,122.56,120.48,116.76,113.13,112.99,109.31,64.35,35.22.
high resolution mass spectral data: HRMS (ESI) calcd for C32H22ClN2O2[M+H]+:501.1364；found501.1366.
Example 12: synthesis of IL
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 8 hours to give the desired compound of formula (IL) as a yellow solid in 53% isolated yield. mp 186-.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.60(s,1H),7.52(d,J＝8.4Hz,1H),7.44-7.30(m,5H),7.28-7.17(m,7H),7.14-7.07(m,2H),6.98(d,J＝8.0Hz,1H),6.89-6.80(m,1H),5.83(t,J＝10.0Hz,1H),3.81(dd,J1＝15.2Hz,J2＝15.6Hz,1H),3.49(dd,J1＝15.2Hz,J2＝15.2Hz,1H).13C NMR(100MHz,CDCl3)193.26,188.08,158.27,146.14,141.71,138.78,135.87,132.29,132.06,131.94,131.09,130.53,129.47,128.86,128.64,127.92,125.29,123.24,122.63,120.63,118.09,116.49,114.49,113.30,112.66,109.31,64.16,35.21.
high resolution mass spectral data: HRMS (ESI) calcd for C33H22N3O2[M+H]+:492.1707；found492.1707.
Example 13: synthesis of IM
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 8 hours to obtain the target product of formula (IM) as a yellow solid in an isolated yield of 76%. MP 248-250℃。
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.77(s,1H),7.53-7.38(m,4H),7.36-7.17(m,H),7.12-7.00(m,2H),6.96(d,J＝8.0Hz,1H),6.86-6.72(m,1H),5.80-5.75(m,1H),3.82(dd,J1＝15.6Hz,J2＝15.6Hz,1H),3.43(dd,J1＝15.6Hz,J2＝15.2Hz,1H).13C NMR(100MHz,CDCl3)192.68,187.88,151.55,146.33,140.98,139.10,135.96,132.24,131.73,131.25,130.73,130.44,130.27,129.18,128.39,128.20,128.12,127.83,125.22,123.07,122.40,120.34,117.81,113.06,109.51,107.73,64.58,35.25.
high resolution mass spectral data: HRMS (ESI) calcd for C30H21N2O2S[M+H]+:473.1318；found473.1319.
Example 14: synthesis of IN
To the reaction tube were added 3- (2- (1H-indol-1-yl) phenyl) -3-oxopropanecarbonitrile (0.2mmol), ZnI in that order under air2(0.01mmol) and toluene (0.2mL) at 80 ℃ for 2 hours, followed by addition of acetylenic ketone (0.2mmol), Cs2CO3(0.4mmol) and DMSO (2.0mL) at 80 ℃ for 8 hours to obtain the desired product of formula (IN) as a yellow solid IN 56% isolated yield. mp 75-77 ℃.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)17.75(s,1H),7.61-7.53(m,3H),7.50-7.44(m,3H),7.41-7.35(m,1H),7.26-7.17(m,2H),7.12-7.01(m,2H),6.94(d,J＝8.0Hz,1H),6.86-6.77(m,1H),5.65-5.54(m,1H),3.70(dd,J1＝15.2Hz,J2＝15.6Hz,1H),3.34(dd,J1＝15.6Hz,J2＝15.6Hz,1H),2.60-2.45(m,2H),1.75-1.65(m,1H),1.26(s,1H),1.13-1.03(m,1H),0.94-0.84(m,1H),0.78-0.68(m,1H),0.60(t,J＝6.4Hz,3H).13C NMR(100MHz,CDCl3)193.65,184.38,163.92,146.42,138.36,135.91,132.65,131.86,131.53,130.94,129.05,128.97,128.33,127.74,125.22,122.75,122.56,120.23,116.23,113.62,111.01,108.95,62.61,21.75,13.27.
high resolution mass spectral data: HRMS (ESI) calcd for C30H27N2O2[M+H]+:447.2067；found447.2067.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (10)
1. An indoline aza eight-membered ring derivative is characterized in that the structure is shown as formula (I):
R1、R2respectively aryl, alkyl substituted aryl, alkoxy substituted aryl and halogen substituted aryl;
R3、R4respectively aryl, alkyl substituted aryl, alkoxy substituted aryl, halogen substituted aryl, cyano substituted aryl, naphthyl, thienyl, alkyl.
2. The indolino aza eight membered ring derivative of claim 1 wherein R1Is phenyl, C1-C10 alkyl substituted phenyl, bromine substituted phenyl; r2Is phenyl, C1-C10 alkoxy substituted phenyl, chloro substituted phenyl; r3Is phenyl, C1-C10 alkoxy substituted phenyl, fluoro substituted phenyl, naphthyl, C1-C10 alkyl; r4Is phenyl, C1-C10 alkoxy substituted phenyl, chloro substituted phenyl, cyano substituted phenyl, thienyl, C1-C10 alkyl.
3. The indolino aza eight membered ring derivative of claim 1 wherein R1Is phenyl, 4-methylphenyl, 4-bromobenzeneA group; r2Is phenyl, 4-methoxyphenyl, 6-chlorophenyl; r3Is phenyl, 3,4, 5-trimethoxyphenyl, p-fluorophenyl, 1-naphthyl or tert-butyl; r4Is phenyl, p-methoxyphenyl, m-chlorophenyl, p-cyanophenyl, 1-thienyl or n-butyl.
4. A synthetic method of indoline aza eight-membered ring derivatives is characterized in that in the first step, in a solvent, raw material indole compounds react under the action of zinc iodide, in the second step, then, acetylenic ketone compounds, solvent and alkali are added into the reaction system in the first step for reaction, and indoline aza eight-membered ring derivatives shown in formula (I) are synthesized; the reaction process is shown as the formula (II):
wherein the content of the first and second substances,
R1、R2respectively aryl, alkyl substituted aryl, alkoxy substituted aryl and halogen substituted aryl;
R3、R4respectively aryl, alkyl substituted aryl, alkoxy substituted aryl, halogen substituted aryl, cyano substituted aryl, naphthyl, thienyl, alkyl.
5. The method of claim 4, wherein the molar ratio of indole compound, zinc iodide, alkynone compound, and base is 1: 0.05: 1: 1-3.
6. The method of synthesis of claim 4, wherein the base comprises NaOH, KOtBu、K2CO3、Cs2CO3And DBU.
7. The synthesis method according to claim 4, wherein the solvent in the first step is one or more of toluene, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and dichloroethane; and in the second step, the solvent is acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide and toluene.
8. The synthesis method according to claim 4, wherein the temperature of the reaction in the first step is room temperature to 80 ℃; the reaction temperature in the second step is 50-110 ℃.
9. The synthesis method according to claim 4, characterized in that the reaction time in the first step is 2-24 hours; the reaction time in the second step is 3 to 19 hours.
10. Use of the indolino aza eight membered ring derivative according to any of claims 1-3 for the preparation of Manzamine a.
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