CN115974893A - Chiral [5+4] indolyazanine-membered ring derivative constructed under catalysis of palladium - Google Patents
Chiral [5+4] indolyazanine-membered ring derivative constructed under catalysis of palladium Download PDFInfo
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 17
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims description 34
- 239000000758 substrate Substances 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000012300 argon atmosphere Substances 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- -1 vinyl cyclic carbonate Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- NNQDMQVWOWCVEM-UHFFFAOYSA-N 1-bromoprop-1-ene Chemical compound CC=CBr NNQDMQVWOWCVEM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 4
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 241000588724 Escherichia coli Species 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960003085 meticillin Drugs 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 2
- YHIWBVHIGCRVLE-UHFFFAOYSA-N 3-bromo-1h-indole Chemical compound C1=CC=C2C(Br)=CNC2=C1 YHIWBVHIGCRVLE-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
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- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- QISSVLCQDNIJCS-UHFFFAOYSA-N 2-fluoro-1h-indole Chemical compound C1=CC=C2NC(F)=CC2=C1 QISSVLCQDNIJCS-UHFFFAOYSA-N 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- VMITYLJHUKSVIC-UHFFFAOYSA-N 3-fluoro-1h-indole Chemical compound C1=CC=C2C(F)=CNC2=C1 VMITYLJHUKSVIC-UHFFFAOYSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
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Abstract
The invention relates to the technical field of medicinal chemistry, discloses a [5+4] indolo-aza-nonatomic ring chiral derivative constructed by palladium catalysis, and also provides a method for preparing the [5+4] indolo-aza-nonatomic ring chiral derivative through intermolecular reaction. The indole-fused cyclic chiral derivative constructed by palladium catalysis has excellent antibacterial activity and wide market application prospect.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a [5+4] indolo-aza nine-membered ring chiral derivative.
Background
Heterocyclic compounds are cyclic molecules containing at least one heteroatom, such as oxygen, nitrogen and other elements. They are present in large amounts in biologically active natural products and appear as the core skeleton of a variety of pharmaceutically important active molecules. The indole heterocyclic skeleton with the chiral center is a key component of a drug molecule, has high biological activity, and occupies a place in drugs in multiple treatment fields such as hypertension resistance, anti-proliferation, antivirus, antitumor and the like. Studies have shown that there are many reports of the synthesis of aza nine-membered ring compounds by intramolecular cyclization reactions, but there are few reports of the synthesis of chiral indolo-heterocyclic nine-membered ring frameworks by intermolecular reactions. Therefore, the method still has strategic significance for developing novel indole heterocyclic chiral compounds.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a [5+4] indolo-aza nine-membered ring chiral derivative constructed by palladium catalysis, a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problem is as follows: a [5+4] indolyazanine-membered ring chiral derivative constructed by palladium catalysis, wherein the chiral derivative has a general formula:
wherein R is 1 Is a phenyl group,One of halogen substituted phenyl, alkyl substituted phenyl, naphthyl and heterocyclic radical;
R 2 is one of phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl and heterocyclic radical;
preferably, alternative structures of the chiral derivative include, but are not limited to:
further, the invention also provides [5+4] constructed by palladium catalysis]A process for the preparation of an indolocarbazenine ring chiral derivative comprising the steps of: adding 5mol% eq Pd to a glove box dried 25mL sealed tube 2 (dba) 3 . CHCl 3 And 15mol% eq chiral ligand L2, sealing the lid, removing from the glove box, adding 2mL dry mesitylene under argon atmosphere, stirring the resulting suspension at 60 ℃ for 30 minutes for coordination, then cooling the reaction to room temperature, adding 1.0eq azadiene substrate 1 and 2.0eq vinyl cyclic carbonate 2 under argon atmosphere, stirring the reaction mixture at room temperature for 2 hours, completing the reaction by monitoring with thin layer chromatography, then directly purifying the reaction mixture with column chromatography to obtain the target product 3, which is the chiral derivative, the reaction formula is:
further, the present invention provides R 1 A process for the preparation of an azadiene substrate 1a which is a phenyl group comprising the steps of:
the method comprises the following steps: 9.53g of indole was weighed into a round bottom flask, and 10.85mL of TsN was added 3 Reacting for 14 hours at 60 ℃ under the condition of condensation reflux, changing the color into dark reddish brown liquid accompanied by solid, adding a small amount of anhydrous methanol, stirring until the solid is separated out, performing suction filtration and drying, and weighing to obtain pink solid I;
step two: 1.2g of I are weighed into the washed rubber covered with a lidRound-bottomed flask with plug, 4mL of dry DCM,0.65mL of benzaldehyde and 1.3mL of BF were added in succession under argon 3 ·Et 2 Reacting at room temperature under the atmosphere of argon for 1h to obtain a yellow solid, adding a small amount of anhydrous methanol, performing ultrasonic treatment until solid particles are separated out, and performing suction filtration and drying to obtain a light yellow solid II;
step three: weigh 0.1eq Pd (OAc) 2 Putting the ligand L1 and 0.15eq into a sealed tube, adding 10mL of dry dichloromethane in the argon atmosphere, reacting for 30min at 40 ℃, and judging that the coordination is successful when the color changes from red to yellow; adding 1eq II, 3eq bromopropylene and 2eq potassium tert-butoxide into a sealed tube under argon atmosphere, reacting for 2h at 40 ℃, monitoring the reaction condition by thin-layer chromatography, adopting a petroleum ether/ethyl acetate system as a developing agent, wherein the ratio of petroleum ether to ethyl acetate is 6: ethyl acetate =10, and dichloromethane 300mL, to obtain an azadiene substrate 1a;
the reaction scheme for preparing the azadiene substrate 1a is:
furthermore, the [5+4] indolyazanine-membered ring chiral derivative constructed by palladium catalysis is used for antibiosis.
The invention provides a [5+4] indolo-aza nonatomic ring chiral derivative which is constructed by palladium catalysis and synthesized by intermolecular reaction and a method for preparing the chiral derivative, wherein the chiral derivative has good antibacterial effect, and the preparation method is simple and convenient, has mild reaction and high yield and has wide market application prospect.
Drawings
FIG. 1 Single crystal structure of the product of example 3.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The reagents and test equipment used in the present invention are conventional commercially available reagents and equipment, unless otherwise noted.
A [5+4] indolocarbazepine nine-membered ring chiral derivative constructed by palladium catalysis has a general formula:
wherein R is 1 Is one of phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl and heterocyclic radical;
R 2 is one of phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl and heterocyclic radical;
alternative structures for the chiral derivatives include, but are not limited to:
[5+4] constructed by palladium catalysis]A process for the preparation of an indolocarbazenine ring chiral derivative comprising the steps of: drying in a glove box 25mL sealed tube, adding 5mol% eq Pd 2 (dba) 3 . CHCl 3 And 15mol% eq chiral ligand L2, sealing the lid, removing from the glove box, adding 2mL dry mesitylene under argon atmosphere, and stirring the resulting suspension at 60 ℃ for 30 minutes for coordination, then cooling the reaction to room temperature, adding 1.0eq azadiene substrate 1 and 2.0eq vinyl cyclic carbonate 2 under argon atmosphere, stirring the reaction mixture at room temperature for 2 hours, completing the reaction by thin layer chromatography monitoring, then directly purifying the reaction mixture by column chromatography to obtain the target product 3, which is the chiral derivative, the reaction formula:
example 1
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4, 7-diphenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (using carbonate in the synthesis of the substrate)
White solid, yield 85%, er 96;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.61(d,J＝7.8Hz,2H),7.45(d,J＝8.4Hz,2H),7.37–7.33(m,4H),7.26–7.23(m,2H),7.22–7.21(m,3H),7.18–7.17(m,2H),7.05(d,J＝8.4Hz,1H),6.94(t,J＝6.6Hz,1H),6.85(d,J＝8.4Hz,2H),6.57(t,J＝7.8Hz,1H),6.08–6.01(m,1H),5.24(d,J＝10.2Hz,1H),5.11(d,J＝16.2Hz,1H),4.98(dd,J＝16.2,6.0Hz,1H),4.94(s,1H),4.85–4.79(m,2H),4.46(d,J＝12.6Hz,1H),3.93–3.88(m,2H),2.10(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):144.1,141.9,140.0,139.9,136.6,135.6,133.8,129.6,128.4,128.0,127.7,127.6,127.2,127.1,126.7,126.4,124.0,123.3,122.2,119.9,117.1,110.9,110.7,69.8,63.2,48.7,45.2,21.3.
this example provides R 1 A process for the preparation of an azadiene substrate 1a which is a phenyl group comprising the steps of:
the method comprises the following steps: 9.53g of indole was weighed into a round bottom flask, and 10.85mL of TsN was added 3 Reacting for 14 hours at 60 ℃ under the condition of condensing reflux, wherein the color is changed into dark reddish brown liquid accompanied with solid, adding a small amount of anhydrous methanol, stirring until the solid is separated out, performing suction filtration and drying, and weighing to obtain pink solid I;
step two: weigh 1.2g of I into a washed round bottom flask with rubber stopper, add 4mL of dry DCM,0.65mL of benzaldehyde, and 1.3mL of BF in that order under argon 3 ·Et 2 O, reacting at room temperature under argon atmosphere, changing into yellow solid after 1h, adding a small amount of anhydrous methanol andperforming ultrasonic treatment until solid particles are separated out, and performing suction filtration and drying to obtain a light yellow solid II;
step three: weigh 0.1eq Pd (OAc) 2 Putting the ligand L1 and 0.15eq into a sealed tube, adding 10mL of dry dichloromethane in an argon atmosphere, reacting for 30min at 40 ℃, and judging that the coordination is successful when the color turns yellow from red; adding 1eq II, 3eq bromopropylene and 2eq potassium tert-butoxide into a sealed tube under argon atmosphere, reacting for 2h at 40 ℃, monitoring the reaction condition by thin-layer chromatography, adopting a petroleum ether/ethyl acetate system as a developing agent, wherein the ratio of petroleum ether to ethyl acetate is 6: ethyl acetate =10, and dichloromethane 300mL, to obtain an azadiene substrate 1a;
the reaction formula for preparing the azadiene substrate 1a is:
example 2
The chiral derivative of [5+4] indolyazanonacyclic ring in this example is (R, Z) -12-allyl-7- (3-fluorophenyl) -4-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (the substrate was synthesized using carbonate, 3-fluoroindole (the rest of the examples not illustrated here used indole)).
White solid, yield 86%, er 97;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.62(d,J＝8.4Hz,2H),7.47(d,J＝6.6Hz,2H),7.37–7.31(m,4H),7.25–7.22(m,1H),7.18–7.14(m,1H),7.00(d,J＝7.8Hz,1H),6.97(d,J＝7.8Hz,1H),6.94(d,J＝7.2Hz,1H),6.93–6.86(m,4H),6.62(t,J＝7.8Hz,1H),6.04–5.97(m,1H),5.21(d,J＝10.2Hz,1H),5.07(d,J＝17.4Hz,1H),4.96(s,1H),4.91(dd,J＝16.8,6.0Hz,1H),4.82(dd,J＝15.0,7.8Hz,1H),4.79–4.75(m,1H),4.45(d,J＝13.2Hz,1H),3.91–3.85(m,2H),2.14(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):162.5(C–F, 1 J C–F ＝244.3Hz),144.3,143.0(C–F, 3 J C–F ＝7.2Hz),141.6,139.7,136.5,135.6,133.7,129.7,129.0(C–F, 3 J C–F ＝7.2Hz),128.4,128.1,127.7,127.4,126.3,123.7,123.4,122.7,121.8,120.1,117.1,114.0(C–F, 2 J C–F ＝23.1Hz),113.5(C–F, 2 J C–F ＝20.2Hz),110.8,110.5,69.3,63.2,48.7,45.2,21.3.
example 3
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-7- (3-bromophenyl) -4-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (the substrate was synthesized using carbonate, 3-bromoindole (the remaining examples not illustrated here all used indole)).
White solid, yield 88%, ee > 99;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.62(d,J＝7.8Hz,2H),7.55(s,1H),7.46(d,J＝9.0Hz,1H),7.40–7.37(m,2H),7.27–7.23(m,5H),7.21–7.19(m,2H),7.06(d,J＝8.4Hz,1H),6.95(t,J＝7.8Hz,1H),6.88(d,J＝7.8Hz,2H),6.53(t,J＝7.8Hz,1H),6.08–6.02(m,1H),5.24(d,J＝10.2Hz,1H),5.12(d,J＝17.4Hz,1H),4.98(dd,J＝16.8,6.0Hz,1H),4.88(s,1H),4.85–4.80(m,2H),4.40(d,J＝12.6Hz,1H),3.91–3.87(m,2H),2.14(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):144.3,142.1,140.8,139.7,136.5,135.6,133.7,130.9,129.9,129.7,129.5,128.4,127.64,127.59,127.0,126.8,124.9,123.4,122.5,122.2,120.0,117.1,110.73,110.66,69.9,63.0,48.4,45.2,21.4.
the single crystal data for the product of example 3 is shown in figure 1 and table 1.
Table 1 single crystal data table for example 3 product
Example 4
The chiral derivative of [5+4] indolyazanonacyclic ring in this example is (S, Z) -12-allyl-7- (2-fluorophenyl) -4-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (the substrate was synthesized using carbonate, 2-fluoroindole (the rest of the examples not illustrated here used indole)).
White solid, yield 77%, er 93;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.72(d,J＝7.8Hz,2H),7.67(t,J＝7.2Hz,1H),7.37(d,J＝8.4Hz,1H),7.33–7.32(m,2H),7.30–7.24(m,5H),7.21(d,J＝7.8Hz,1H),7.09(t,J＝7.2Hz,1H),6.99(t,J＝7.2Hz,1H),6.95(d,J＝8.4Hz,2H),6.92(t,J＝9.6Hz,1H),6.34(t,J＝8.4Hz,1H),6.09–6.02(m,1H),5.24(d,J＝10.8Hz,1H),5.15–5.12(m,2H),5.05(dd,J＝16.8,6.0Hz,1H),4.88–4.84(m,1H),4.76(dd,J＝14.4,7.8Hz,1H),4.46(d,J＝12.0Hz,1H),3.98–3.94(m,2H),2.22(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):160.7(C–F, 1 J C–F ＝251.6Hz),144.0,142.5,140.0,136.5,135.5,134.8,133.7,129.6,129.4(C–F, 3 J C–F ＝2.9Hz),128.9(C–F, 3 J C–F ＝8.6Hz),128.1,127.8,127.77,127.3(C–F, 2 J C–F ＝13.0Hz),126.4,124.2,123.22,123.19,123.17,121.6,120.0,117.1,115.4(C–F, 2 J C–F =21.7 Hz), 110.8,110.1,67.0,63.7,48.4,45.3,21.4 example 5
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4-phenyl-7-o-tolyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (the substrate was synthesized using carbonate, 2-methylindole (indole is used in the remaining examples not illustrated here)).
White solid, yield 49%, er 95;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.58(d,J＝8.4Hz,2H),7.53(d,J＝7.2Hz,1H),7.35(d,J＝8.4Hz,1H),7.28–7.22(m,7H),7.16(t,J＝7.8Hz,1H),7.07(t,J＝7.8Hz,1H),7.00–6.97(m,2H),6.80(d,J＝8.4Hz,2H),6.32(t,J＝7.2Hz,1H),6.08–6.01(m,1H),5.22(d,J＝11.4Hz,1H),5.12(d,J＝16.8Hz,1H),5.05(dd,J＝16.2,6.0Hz,1H),4.89–4.85(m,1H),4.84(s,1H),4.70(dd,J＝14.4,8.4Hz,1H),4.50(d,J＝12.6Hz,1H),4.05(dd,J＝14.4,8.4Hz,1H),3.89(d,J＝13.2Hz,1H),2.18(s,3H),1.63(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):143.9,143.0,140.0,138.0,137.1,136.1,135.6,134.3,133.6,130.6,129.6,128.9,128.2,127.9,127.5,127.4,126.2,125.6,124.9,124.5,123.2,122.6,119.9,117.2,111.5,110.7,71.8,64.2,48.5,45.4,21.4,20.4.
example 6
The chiral derivative of [5+4] indolocarbazepine nonacyclic ring in this example is (R, Z) -12-allyl-4-phenyl-7-o-tolyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (the substrate was synthesized using carbonate, N-methylindole (indole is used in the rest of the examples not described here)).
White solid, 50% yield, er 93;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.62(d,J＝8.4Hz,2H),7.44(d,J＝6.6Hz,2H),7.36–7.32(m,4H),7.28–7.25(m,3H),7.22–7.17(m,5H),7.03(d,J＝7.2Hz,1H),6.94(t,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,2H),6.57(t,J＝8.4Hz,1H),4.97(s,1H),4.92(dd,J＝15.6,7.8Hz,1H),4.45(d,J＝12.0Hz,1H),3.94(d,J＝13.2Hz,1H),3.89(dd,J＝14.4,9.0Hz,1H),3.74(s,3H),2.12(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):144.1,142.1,140.1,139.9,136.8,136.1,135.9,129.7,128.3,128.0,127.64,127.58,127.02,126.97,126.6,126.4,123.9,123.2,122.1,119.8,110.6,110.0,69.8,63.2,48.4,29.4,21.3.
example 7
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4- (4-fluorophenyl) -7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (4-F carbonate was used for the substrate synthesis).
White solid, yield 76%, er 94;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.60(d,J＝8.4Hz,2H),7.45–7.42(m,2H),7.35(d,J＝8.4Hz,1H),7.24–7.21(m,4H),7.18–7.17(m,2H),7.04–7.01(m,3H),6.93(t,J＝7.2Hz,1H),6.84(d,J＝8.4Hz,2H),6.52(t,J＝8.4Hz,1H),6.04–5.98(m,1H),5.21(d,J＝10.2Hz,1H),5.08(d,J＝16.8Hz,1H),4.94–4.90(m,2H),4.82–4.76(m,2H),4.40(d,J＝12.6Hz,1H),3.91–3.85(m,2H),2.10(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):162.5(C–F, 1 J C–F ＝247.2Hz),161.7,144.1,140.8,139.9,136.5,135.9,135.88,135.6,135.5,133.7,129.6,128.0(C–F, 3 J C–F ＝7.2Hz),127.6(C–F, 3 J C–F ＝2.9Hz),127.1,127.0,126.7,123.9,123.3,122.1,119.9,117.0,115.2(C–F, 2 J C–F ＝21.7Hz),110.9,110.7,69.8,63.2,48.6,45.2,21.3.
example 8
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4- (4-chlorophenyl) -7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (4-chlorocarbonate was used for the substrate synthesis).
White solid, yield 91%, er 94;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.59(d,J＝7.8Hz,2H),7.41(d,J＝9.0Hz,2H),7.35(d,J＝7.8Hz,1H),7.32(d,J＝8.4Hz,2H),7.25–7.22(m,4H),7.18–7.17(m,2H),7.02(d,J＝7.8Hz,1H),6.93(t,J＝6.6Hz,1H),6.85(d,J＝7.2Hz,2H),6.56(t,J＝8.4Hz,1H),6.05–5.99(m,1H),5.22(d,J＝10.2Hz,1H),5.08(d,J＝17.4Hz,1H),4.95–4.91(m,2H),4.83–4.76(m,2H),4.40(d,J＝12.6Hz,1H),3.91–3.85(m,2H),2.11(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):144.2,140.7,139.8,138.3,136.5,135.6,135.5,133.9,133.7,129.6,128.5,127.6,127.0,126.8,123.9,123.4,122.1,120.0,117.1,110.9,110.7,69.9,63.0,48.6,45.2,21.3.
example 9
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4- (3-fluorophenyl) -7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (3-fluoro carbonate was used for the substrate synthesis).
White solid, yield 91%, er 95;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.61(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,1H),7.32–7.29(m,1H),7.24–7.22(m,5H),7.20–7.18(m,2H),7.08–7.05(m,1H),7.03–6.99(m,2H),6.93(t,J＝7.2Hz,1H),6.87(d,J＝7.8Hz,2H),6.53(t,J＝7.8Hz,1H),6.06–6.00(m,1H),5.23(d,J＝10.2Hz,1H),5.09(d,J＝16.8Hz,1H),4.96–4.93(m,2H),4.83–4.78(m,2H),4.41(d,J＝13.2Hz,1H),3.91–3.86(m,2H),2.12(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):162.8(C–F, 1 J C–F ＝244.3Hz),144.3,142.2(C–F, 3 J C–F ＝8.6Hz),140.9,139.8,136.6,135.6,133.7,129.8(C–F, 3 J C–F ＝8.8Hz),129.7,128.2,127.7,127.0,126.8,123.9,123.4,122.1,122.0,121.9,120.0,117.1,114.8(C–F, 2 J C–F ＝21.7Hz),113.5(C–F, 2 J C–F ＝23.1Hz),110.8,110.7,69.9,63.0,48.5,45.2,21.3.
example 10
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4- (2-fluorophenyl) -7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (2-fluoro carbonate was used for the substrate synthesis).
White solid, yield 97%, er 94;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.66(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,1H),7.29–7.21(m,5H),7.21–7.18(m,2H),7.05–7.00(m,3H),6.94–6.91(m,3H),6.73(t,J＝7.8Hz,1H),6.32(t,J＝8.4Hz,1H),6.07–6.01(m,1H),5.23(d,J＝10.2Hz,1H),5.10(d,J＝17.4Hz,1H),5.04(s,1H),4.98(dd,J＝16.2,6.0Hz,1H),4.83–4.79(m,1H),4.77(dd,J＝15.0,7.2Hz,1H),4.35(d,J＝12.0Hz,1H),3.95(dd,J＝14.4,8.4Hz,1H),3.87(d,J＝12.0Hz,1H),2.20(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):159.6(C–F, 1 J C–F ＝247.2Hz),144.1,139.9,139.0,136.8,135.6,133.7,131.0,130.4(C–F, 3 J C–F ＝3.0Hz),129.7,129.4(C–F, 3 J C–F ＝8.6Hz),128.6(C–F, 2 J C–F ＝14.5Hz),127.8,127.6,127.0,126.7,123.9,123.8,123.3,122.2,119.9,117.1,115.7(C–F, 2 J C–F ＝21.7Hz),110.7,110.6,70.0,63.8,48.1,45.3,21.4.
example 11
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4- (2-bromophenyl) -7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (2-bromocarbonate was used for the substrate synthesis).
White solid, yield 99%, er 87;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.65(d,J＝7.8Hz,2H),7.53(d,J＝7.2Hz,1H),7.37(d,J＝8.4Hz,1H),7.28–7.23(m,6H),7.16–7.09(m,2H),7.01(d,J＝8.4Hz,1H),6.93–6.90(m,3H),6.25(d,J＝6.0Hz,1H),6.09–6.02(m,2H),5.25(d,J＝10.2Hz,1H),5.16(d,J＝17.4Hz,1H),5.03(s,1H),5.00(dd,J＝16.8,6.0Hz,1H),4.85–4.82(m,1H),4.75(dd,J＝15.6,7.8Hz,1H),4.36(d,J＝12.0Hz,1H),3.96(dd,J＝15.6,9.0Hz,1H),3.86(d,J＝12.6Hz,1H),2.23(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):144.1,144.0,141.8,139.8,137.0,135.7,135.6,133.7,132.5,130.7,130.2,129.8,129.1,127.9,127.7,127.0,126.82,126.77,123.8,123.4,122.2,121.5,119.9,117.3,110.7,110.4,70.3,63.6,48.0,45.3,21.4.
example 12
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-4- (4-ethylphenyl) -7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (4-ethylcarbonate was used for the substrate synthesis).
White solid, yield 78%, er 97;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.62(d,J＝8.4Hz,2H),7.42(d,J＝7.8Hz,2H),7.37(d,J＝8.4Hz,1H),7.27–7.25(m,1H),7.24–7.19(m,7H),7.06(d,J＝7.8Hz,1H),6.95(t,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,2H),6.58(t,J＝7.8Hz,1H),6.08–6.02(m,1H),5.24(d,J＝10.2Hz,1H),5.12(d,J＝17.4Hz,1H),4.99(dd,J＝17.4,7.2Hz,1H),4.96(s,1H),4.86–4.80(m,2H),4.47(d,J＝12.6Hz,1H),3.92–3.88(m,2H),2.70(q,J＝7.8Hz,2H),2.11(s,3H),1.29(t,J＝7.8Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):144.1,144.0,141.6,140.0,137.1,136.5,135.6,133.8,129.6,127.8,127.7,127.5,127.1,126.6,126.3,124.0,123.3,122.1,119.9,117.0,110.9,110.7,69.7,63.1,48.8,45.2,28.5,21.3,15.5.
example 13
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -12-allyl-9-methoxy-4, 7-diphenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (the substrate was synthesized using carbonate, 5-bromoindole (the remaining examples not illustrated here all used indole)).
White solid, yield 68%, er 95;
1 H NMR(600MHz,CDCl3)δ(ppm):7.62(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),7.37–7.31(m,3H),7.25–7.19(m,6H),6.90(dd,J＝9.0,3.0Hz,1H),6.86(d,J＝8.4Hz,2H),6.58(t,J＝7.8Hz,1H),6.45(d,J＝3.0Hz,1H),5.98–6.06(m,1H),5.23(d,J＝10.2Hz,1H),5.09(d,J＝17.4Hz,1H),4.96(s,1H),4.93(dd,J＝17.4,6.6Hz,1H),4.83(dd,J＝15.0,7.8Hz,1H),4.77–4.73(m,1H),4.48(d,J＝12.0Hz,1H),3.97(d,J＝12.0Hz,1H),3.91(dd,J＝14.4,9.0Hz,1H),3.52(s,3H),2.12(s,3H).
13 C NMR(151MHz,CDCl3)δ(ppm):153.7,144.1,141.8,139.8,136.5,135.6,133.9,130.6,129.6,128.3,128.0,127.7,127.6,127.2,127.1,126.7,126.3,124.3,116.9,114.1,111.6,110.3,103.1,69.8,63.1,55.4,48.7,45.3,21.3.
example 14
The [5+4] indolyazanonacyclic chiral derivative of this example is (R, Z) -4- (1, 1' -biphenyl-4-yl) -12-allyl-7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (4-phenylcarbonate was used for the substrate synthesis).
White solid, yield 85%, er 96;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.65(d,J＝7.8Hz,2H),7.62–7.59(m,4H),7.58–7.56(m,2H),7.49–7.46(m,2H),7.39–7.36(m,2H),7.25–7.23(m,1H),7.22–7.20(m,3H),7.19–7.17(m,2H),7.06(d,J＝7.8Hz,1H),6.94(t,J＝8.4Hz,1H),6.85(d,J＝7.8Hz,2H),6.66(t,J＝7.2Hz,1H),6.07–6.01(m,1H),5.23(d,J＝10.2Hz,1H),5.10(d,J＝16.8Hz,1H),4.99–4.95(m,2H),4.85(dd,J＝15.6,7.8Hz,1H),4.83–4.79(m,1H),4.50(d,J＝13.2Hz,1H),3.95–3.89(m,2H),2.09(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):144.1,141.3,140.6,140.4,139.9,138.6,136.5,135.64,135.61,133.8,129.7,128.8,127.7,127.6,127.5,127.1,127.01,126.95,126.8,126.7,124.0,123.3,122.2,119.9,117.1,110.9,110.7,69.8,63.1,48.8,45.2,21.3.
example 15
The chiral derivative of [5+4] indolyazanonacyclic ring in this example is (R, Z) -12-allyl-4- (3, 4-dimethoxyphenyl) -7-phenyl-1-toluenesulfonyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxa-aza [4,3-b ] indole (3, 4-dimethoxycarbonate was used as a substrate for synthesis)
White solid, yield 77%, er 91;
1 H NMR(600MHz,CDCl 3 )δ(ppm):7.58(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,1H),7.24–7.21(m,1H),7.21–7.17(m,6H),7.11(d,J＝8.4Hz,1H),7.03(d,J＝8.4Hz,1H),6.92(t,J＝6.6Hz,1H),6.85(d,J＝8.4Hz,1H),6.83(d,J＝7.2Hz,2H),6.58(t,J＝7.8Hz,1H),6.05–5.98(m,1H),5.21(d,J＝10.2Hz,1H),5.07(d,J＝17.4Hz,1H),4.95–4.92(m,2H),4.83(dd,J＝14.4,7.2Hz,1H),4.79–4.76(m,1H),4.42(d,J＝12.6Hz,1H),3.92–3.85(m,8H),2.07(s,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):148.9,148.5,144.0,141.2,140.0,136.3,135.6,135.3,133.8,132.9,129.6,127.6,127.5,127.0,126.7,125.8,123.9,123.3,122.0,119.90,118.99,117.0,111.1,110.7,109.4,69.7,63.4,55.9,55.8,48.9,45.2,21.3.
example 16
The [5+4] indolocarbazepine nonacyclic chiral derivative of this example is (R, Z) -12-allyl-4-naphthalen-2-yl-7-phenyl-1-tosyl-2, 5,7, 12-tetrahydro-1H- [1,5] oxazolo [4,3-b ] indole (2-naphthalenecarbonate was used as the substrate for synthesis)
White solid, yield 72%, er 95;
1 H NMR(600 MHz,CDCl 3 )δ(ppm):8.03(s,1H),7.88–7.85(m,2H),7.84(d,J＝9.0 Hz,1H),7.63–7.61(m,3H),7.54–7.50(m,2H),7.40(d,J＝7.8 Hz,1H),7.28–7.26(m,1H),7.21–7.18(m,5H),7.10(d,J＝7.8 Hz,1H),6.97(t,J＝7.2 Hz,1H),6.81(d,J＝7.2 Hz,2H),6.76(t,J＝8.4 Hz,1H),6.11–6.05(m,1H),5.27(d,J＝10.2 Hz,1H),5.15(d,J＝16.2 Hz,1H),5.04(dd,J＝16.2,6.0 Hz,1H),4.96(s,1H),4.92(dd,J＝15.0,7.8 Hz,1H),4.87–4.84(m,1H),4.61(d,J＝13.2 Hz,1H),4.02(d,J＝12.6 Hz,1H),3.96(dd,J＝15.0,9.0 Hz,1H),2.04(s,3H).
13 C NMR(151 MHz,CDCl 3 )δ(ppm):144.1,141.6,139.8,136.9,136.5,135.70,135.67,133.8,133.4,132.9,129.6,128.3,127.9,127.7,127.6,127.52,127.47,127.2,126.7,126.3,126.2,125.9,123.99,123.97,123.4,122.2,119.9,117.1,110.9,110.8,70.0,63.2,48.8,45.3,21.3.
the advantageous effects of the present invention will be specifically described below by way of test examples.
Test example 1, antitumor study, [5+4] indole-aza nine membered ring chiral derivative bacteriostatic activity test:
1. purpose of the experiment:
the MIC values of test compounds (compounds 7, 8 and 9) against clinically isolated pathogenic bacteria (including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-sensitive Staphylococcus epidermidis (MSSE) gram-positive bacteria, and gram-positive bacteria such as Klebsiella pneumoniae (ESBLs +), klebsiella pneumoniae (ESBLs-), escherichia coli (ESBLs +), escherichia coli (ESBLs-), escherichia coli standard strain (ATCC 25922), staphylococcus aureus standard strain (ATCC 29213) and the like collected in hospitals in the region of 2-3 years are determined by agar plate double dilution method, and the total MIC values are about 24 strains.
2. The experimental basis is as follows:
the determination of the Minimum Inhibitory Concentration (MIC) was performed using the agar double dilution method recommended by the national Committee for standardization of Clinical laboratories (Clinical and Laboratory Standards Institute CLSI).
3. The experimental method comprises the following steps:
adding 1mL of test solution into a sterile plate, adding 14mL of a melted 50 ℃ MHA culture medium, and uniformly mixing to ensure that the final concentration of the medicine contained in each plate is 128, 64, 32, 16 and 8 mu g/mL in sequence; after cooling, inoculating bacteria by using a multi-point inoculating instrument, wherein the inoculation bacterial amount is about 104CFU/mL, covering a dish cover, putting the dish cover in an incubator, and incubating for 20-24h at 36 +/-1 ℃. And after the culture is finished, carrying out visual observation, wherein the lowest sample concentration in which no bacteria grow in the plate is the Minimum Inhibitory Concentration (MIC). Meanwhile, a blank bacteria control without any sample is set.
4. The experimental results are as follows: MIC values of compounds 7, 8 and 9 to E.coli standard strain (ATCC 25922) were 128. Mu.g/mL.
Showing activity thereto.
The compound prepared by the invention can effectively inhibit an escherichia coli standard strain (ATCC 25922) and has good antibacterial activity. The antibacterial effect is also achieved for other compounds, the experimental method and the final effect are the same, and in order to reduce repeated contents, the experimental contents of other compounds are not listed one by one.
While the present invention has been described with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. The [5+4] indolyazanine-membered ring chiral derivative is constructed by palladium catalysis, and is characterized in that the chiral derivative has a general formula:
wherein R is 1 Is one of phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl and heterocyclic radical;
R 2 is one of phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl and heterocyclic radical.
2. The chiral derivative of [5+4] indolo-aza nine-membered ring constructed by palladium catalysis as claimed in claim 1, wherein the optional structures of the chiral derivative include but are not limited to:
3. [5+4] constructed by palladium catalysis according to claim 1 or 2]The preparation method of the indolocarbazenine-membered ring chiral derivative is characterized by comprising the following steps: adding 5mol% eq Pd to a glove box dried 25mL sealed tube 2 (dba) 3 . CHCl 3 And 15mol% eq chiral ligand L2, sealing the lid, removing from the glove box, adding 2mL dry mesitylene under argon atmosphere, stirring the resulting suspension at 60 ℃ for 30 minutes for coordination, then cooling the reaction to room temperature, adding 1.0eq azadiene substrate 1 and 2.0eq vinyl cyclic carbonate 2 under argon atmosphere, stirring the reaction mixture at room temperature for 2 hours, completing the reaction by monitoring with thin layer chromatography, then directly purifying the reaction mixture with column chromatography to obtain the corresponding target product 3, which is the chiral derivative, the reaction formula is:
4. [5+4] constructed by palladium catalysis according to claim 3]Indoloaza nine-membered ring chiral derivatives, characterized in that R in said azabiene substrate 1 1 Is phenyl, the azadiene substrate 1 is a substrate 1a, and the preparation method specifically comprises the following steps:
the method comprises the following steps: 9.53g of indole was weighed into a round bottom flask, and 10.85mL of TsN was added 3 Reacting for 14 hours at 60 ℃ under the condition of condensation reflux, changing the color into dark reddish brown liquid accompanied by solid, adding a small amount of anhydrous methanol, stirring until the solid is separated out, performing suction filtration and drying, and weighing to obtain pink solid I;
step two: weigh 1.2g of I into a washed round bottom flask with rubber stopper, add 4mL of dry DCM,0.65mL of benzaldehyde, and 1.3mL of BF in that order under argon 3 ·Et 2 Reacting at room temperature under the atmosphere of argon for 1h to obtain a yellow solid, adding a small amount of anhydrous methanol, performing ultrasonic treatment until solid particles are separated out, and performing suction filtration and drying to obtain a light yellow solid II;
step three: weigh 0.1eq Pd (OAc) 2 Putting the ligand L1 and 0.15eq into a sealed tube, adding 10mL of dry dichloromethane in an argon atmosphere, reacting for 30min at 40 ℃, and judging that the coordination is successful when the color turns yellow from red; adding 1eq II, 3eq bromopropene and 2eq potassium tert-butoxide into a sealed tube under argon atmosphere, and reacting at 40 deg.C for 2hAnd monitoring the reaction condition by thin-layer chromatography, wherein a petroleum ether/ethyl acetate system is adopted as a developing agent, the ratio of petroleum ether to ethyl acetate is 6: ethyl acetate =10, and dichloromethane 300mL, to obtain an azadiene substrate 1a;
the reaction formula for preparing the azadiene substrate 1a is:
5. the chiral derivative of [5+4] indolo-aza nine-membered ring constructed under catalysis of palladium as claimed in claim 4, wherein the chiral derivative of [5+4] indolo-aza nine-membered ring constructed under catalysis of palladium is used for antibiosis.
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Non-Patent Citations (1)
| Title |
|---|
| HYUN JI JEON: "Divergent Asymmetric Synthesis of Chiral Spiroheterocycles through Pd-Catalyzed Enantio- and Diastereoselective [3 + 2] Spiroannulation", 《ORG. LETT. 》, vol. 24, 12 December 2022 (2022-12-12), pages 9189 - 9193 * |
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