CN114044771B - Compound with 5-hydroxyfuran-2 (5H) -ketone skeleton and preparation method thereof - Google Patents
Compound with 5-hydroxyfuran-2 (5H) -ketone skeleton and preparation method thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000758 substrate Substances 0.000 claims abstract description 18
- 239000000654 additive Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 9
- 230000000996 additive effect Effects 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000017281 sodium acetate Nutrition 0.000 claims abstract 2
- 239000001632 sodium acetate Substances 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- DUAZKLYNTLDKQK-UHFFFAOYSA-N 5-hydroxy-2(5h)-furanone Chemical group OC1OC(=O)C=C1 DUAZKLYNTLDKQK-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- -1 indole compound Chemical class 0.000 abstract description 68
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 9
- 238000005805 hydroxylation reaction Methods 0.000 abstract description 6
- 238000007273 lactonization reaction Methods 0.000 abstract description 6
- 238000013508 migration Methods 0.000 abstract description 6
- 230000005012 migration Effects 0.000 abstract description 6
- 238000006772 olefination reaction Methods 0.000 abstract description 6
- 230000033444 hydroxylation Effects 0.000 abstract description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 5
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 abstract 1
- ICGWWCLWBPLPDF-UHFFFAOYSA-N furan-2-ol Chemical class OC1=CC=CO1 ICGWWCLWBPLPDF-UHFFFAOYSA-N 0.000 abstract 1
- 229910052703 rhodium Inorganic materials 0.000 abstract 1
- 239000010948 rhodium Substances 0.000 abstract 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 246
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- 238000003818 flash chromatography Methods 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 42
- 239000000741 silica gel Substances 0.000 description 42
- 229910002027 silica gel Inorganic materials 0.000 description 42
- 239000007787 solid Substances 0.000 description 38
- 239000003208 petroleum Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 230000003321 amplification Effects 0.000 description 3
- 238000010523 cascade reaction Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- KHSREFIWULNDAB-YCUBLIQYSA-N Sorgolactone Chemical compound O([C@@H]1C2=C(C[C@@H]11)CCC[C@@H]2C)C(=O)\C1=C\O[C@@H]1OC(=O)C(C)=C1 KHSREFIWULNDAB-YCUBLIQYSA-N 0.000 description 1
- KHSREFIWULNDAB-MRZMDFQOSA-N Sorgolactone Natural products O(/C=C/1\C(=O)O[C@H]2[C@@H]\1CC1=C2[C@@H](C)CCC1)[C@@H]1OC(=O)C(C)=C1 KHSREFIWULNDAB-MRZMDFQOSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical group O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- WKHWQWGTSSQIRF-UHFFFAOYSA-N lambertellol A Natural products O1C(=O)C(C)=CC11C(O)C2=CC=CC(O)=C2C(=O)C1 WKHWQWGTSSQIRF-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 230000007226 seed germination Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention provides a compound with a 5-hydroxyfuran-2 (5H) -ketone skeleton and a preparation method thereof, belonging to the technical field of organic synthesis. The invention adopts rhodium to catalyze C-H olefination/guide group migration/lactonization/C-H hydroxylation series reaction to prepare a series of 5-hydroxyfuran-containing products2 (5H) -ketone skeleton, the reaction conditions are as follows: indole compound I and 4-hydroxy-2-alkynoate compound II are used as substrates, and [ Cp ] RhCl is used as substrate 2 ] 2 The target compound IV with the 5-hydroxyfuran-2 (5H) -ketone skeleton is obtained by reacting a catalyst, sodium acetate as an additive and acetone as a solvent in an air atmosphere. The synthesis method provided by the invention has the advantages of wide substrate application range, high regioselectivity and stereoselectivity, good yield, good functional group tolerance, economic reaction steps, high bonding efficiency, mild reaction conditions and the like. The reaction equation involved in the synthesis reaction of the present invention is as follows:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a compound with a 5-hydroxyfuran-2 (5H) -ketone skeleton and a preparation method thereof.
Background
Studies have shown that many drugs and active natural product molecules have furan-2 (5H) -one backbones, and as shown below, rofecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor useful in the treatment of osteoarthritis and rheumatoid arthritis, as well as in the relief of acute pain and in the treatment of primary dysmenorrhea. The natural product Sorgolactone has the activity of promoting seed germination, the natural product lambertellol A has the antibacterial activity, and the natural product KallolideA has the anti-inflammatory activity. Therefore, the compound with the furan-2 (5H) -ketone structure has potential pharmacological application value. Therefore, developing a high-efficiency preparation method for synthesizing furan-2 (5H) -ketone compounds has important theoretical value and application value.
Disclosure of Invention
The invention aims to provide a compound with a 5-hydroxyfuran-2 (5H) -ketone skeleton and a preparation method thereof. The synthesis method has the advantages of wide substrate application range, high regioselectivity, high stereoselectivity, good yield, good functional group tolerance, economic reaction steps, high bonding efficiency, mild reaction conditions and the like.
One of the purposes of the present invention is to provide a preparation method of a compound with a 5-hydroxyfuran-2 (5H) -one skeleton, wherein the structural formula of the compound with the 5-hydroxyfuran-2 (5H) -one skeleton is shown as a formula < IV >, and the preparation method comprises the following steps:
by means of<Ⅰ>Indole compounds and formula<Ⅱ>The 4-hydroxy-2-alkynoate compound is taken as a substrate and [ Cp ] RhCl is taken as a substrate 2 ] 2 Is prepared by reacting catalyst, naOAc as additive and acetone as solvent in air atmosphere to obtain the formula<Ⅳ>A compound shown in the specification;
the reaction formula involved in the method is as follows:
wherein R is 1 Represents a substituent at any position on the phenyl ring selected from the following groups: hydrogen, halogen, alkyl, alkoxy, 3-6 membered heterocyclic ring containing one N, O or S atom, cyano, ester group;
R 2 selected from the following groups: hydrogen, substituted or unsubstituted alkyl;
R 3 selected from the following groups: substituted or unsubstituted alkyl;
R 4 selected from the following groups: substituted or unsubstituted alkyl, aryl;
R 5 selected from the following groups: an alkyl group;
the substitution means that one or more hydrogen atoms on the group are substituted with any group selected from the group consisting of: phenyl.
Further, the halogen includes F, cl, br or I.
Further, the alkyl group comprises methyl, ethyl, isopropyl, n-butyl, tert-butyl or n-pentyl; the alkoxy group comprises methoxy or ethoxy; the substituted alkyl group comprises benzyl; the aryl group includes phenyl, p-methyl substituted phenyl or p-chloro substituted phenyl.
Further, the 3-6 membered heterocyclic ring containing one N, O or S atom includes the following groups:
further, the reaction conditions are as follows: the reaction temperature is 25 ℃, and the reaction time is 5-24h.
Further, the molar ratio of the compound I to the compound II is 1:1.3.
Further, the catalyst is used in an amount of 1 to 10% by mole, preferably 5% by mole (in the example, 5% by mole) of the compound I.
Further, the molar ratio of the additive to compound I is 1:1.
It is another object of the present invention to provide a compound having a 5-hydroxyfuran-2 (5H) -one skeleton produced by the above method. As shown in the examples of the present invention, the present invention provides a series of compounds that have been successfully synthesized and characterized.
The beneficial effects of the invention are as follows:
the invention develops a series of rhodium-catalyzed C-H olefination/guide group migration/lactonization/C-H hydroxylation reaction, and a series of compounds with 5-hydroxyfuran-2 (5H) -ketone skeletons are successfully prepared. The synthesis reaction has the advantages of wide substrate application range, high regioselectivity and stereoselectivity, good yield, good functional group tolerance, economic reaction steps, high bonding efficiency, mild reaction conditions and the like, and the reaction can be amplified to gram scale and has good application value.
Detailed Description
In order that the objects, technical solutions and advantages of the present invention will become more apparent, the following detailed description of the present invention will be made with reference to the examples, which are given by way of illustration and explanation only, and are not intended to limit the present invention. Some non-essential modifications and adaptations of the invention according to the foregoing summary will still fall within the scope of the invention.
Example 1
Optimization of reaction conditions:
using indole 1aa and 4-hydroxy non-2-alkynoic acid methyl ester 2aa as template substrates, the reaction conditions were optimized according to the procedure shown in Table 1.
First, 1aa and 2aa were reacted in Acetone (Acetone) under an air atmosphere at 25℃for 5h under the catalysis of a series of metal catalysts using NaOAc as an additive (SEQ ID NO: 1-6). The results indicate that when [ Cp ] RhCl is used 2 ] 2 As a catalyst, the desired C-H olefination/director migration/lactonization/C-H hydroxylation tandem reaction product 4aa was obtained in 77% yield with the concomitant formation of a small amount of by-product 3aa (SEQ ID NO: 6).
Then, respectively using [ Cp ] RhCl 2 ] 2 And NaOAc as catalyst and additive the solvent was screened (nos. 7-11), and the results indicated that acetone was still the optimal reaction solvent.
Subsequently, various additives (Ser. No. 12-14) were examined in the optimal reaction solvent acetone, in contrast to NaOAc, which is still the most effective additive.
Finally, blank experiments (numbers 15 and 16) were performed. The results indicate that [ Cp ] RhCl 2 ] 2 And NaOAc are indispensable, [ Cp ] RhCl 2 ] 2 The NaOAc catalytic system is the key to successfully achieve this C-H olefination/director migration/lactonization/C-H hydroxylation tandem reaction.
TABLE 1 optimization of reaction conditions a
a Reaction conditions: 1aa (0.25 mmol), 2aa (0.325 mmol), catalyst (5 mol%), additive (0.25 mmol), air (1 atm), solvent (4.0 mL), reaction temperature 25℃for 5h; b refers to isolated yields. N-Pent is N-pentyl, acetone is Acetone, DCM is dichloromethane, DCE is 1, 2-dichloroethane, THF is tetrahydrofuran, etOH is ethanol, DMF is N, N-dimethylformamide, trace represents trace amounts.
Example 2
Investigation of the application range of the substrate:
under the above-mentioned optimal reaction conditions (SEQ ID NO: 6), a series of compounds 4 having a 5-hydroxyfuran-2 (5H) -one skeleton were prepared by examining the substrate application range of rhodium-catalyzed C-H olefination/director migration/lactonization/C-H hydroxylation tandem reaction as shown in Table 2. Firstly, 4-hydroxy-nono-2-methyl alkynoate 2aa is taken as a coupling component, the application range of indole substrates is examined, the compound 4aa-4be is synthesized, and the yield is counted. Then, the application range of the 4-hydroxy-2-alkynoate substrate is examined, the compound 4bf-4bn is synthesized, and the yield is counted. The examination results are shown in Table 2.
The specific method comprises the following steps: indole 1 (0.25 mmol), [ Cp ] RhCl was added sequentially to a 25mL schlenk reaction tube 2 ] 2 (5 mol%) and NaOAc (0.25 mmol), and then a solution of 4-hydroxy-2-alkynoate 2 (0.325 mmol) in acetone (4.0 mL) was added thereto, and then the reaction tube was closed with a rubber stopper, and the resulting reaction mixture was stirred at 25℃for the reaction time shown in Table 2. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the residue was purified by flash chromatography on silica gel to give the desired product 4.
TABLE 2 substrate application Range a,b
a Reaction conditions: substrate 1 (0.25 mmol), substrate 2 (0.325 mmol), [ Cp ] RhCl 2 ] 2 (5 mol%), naOAc (0.25 mmol), air (1 atm), acetone (4.0 mL), 25℃for 5-24h; b the yield was isolated. n-Pent is n-pentyl, et is ethyl, n-Bu is n-butyl, and Ph is phenyl.
The results show that the rhodium-catalyzed C-H olefination/guide group migration/lactonization/C-H hydroxylation series reaction provided by the invention has the advantages of wide substrate application range, high regioselectivity and stereoselectivity, good yield, good functional group tolerance, economic reaction steps, high bond formation efficiency, mild reaction conditions and the like, and can be used for efficiently synthesizing a series of compounds 4 with 5-hydroxyfuran-2 (5H) -ketone skeletons.
Example 3
Gram scale amplification reaction experiment:
gram-scale amplification was performed according to the reaction conditions shown in the following reaction scheme, and indole 1aa (6 mmol) and [ Cp. RTM. RhCl were sequentially added to a 100mL round bottom flask 2 ] 2 (5 mol%) and NaOAc (6 mmol), then an acetone solution (40.0 mL) containing methyl 4-hydroxynon-2-alkynoate 2aa (7.8 mmol) was added thereto, and the resulting reaction mixture was left open to air at 25℃and stirred for 20 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the obtained residue was purified by flash chromatography on silica gel (petroleum/ethyl acetate: 8/1. Fwdarw. Petroleum/ethyl acetate: 4/1), whereby 1.70g of a yellow amorphous solid was obtained in 79% yield, which was the objective product 4aa. The amplification reaction experiment results prove that: the reaction can be scaled up to gram scale, further demonstrating the utility of such reactions.
Example 4
Specific characterization of a series of compounds with a 5-hydroxyfuran-2 (5H) -one backbone (compounds one to forty-six) prepared in examples 2 and 3 above:
the characterization method adopts a hydrogen spectrum, a carbon spectrum and a high-resolution mass spectrum, and the characterization result of the obtained series of compounds is as follows:
compound one (4 aa):
5-hydroxy-4- (1H-indol-2-yl) -N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-4-(1H-indol-2-yl)-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (69.1 mg, 77% yield), mp (melting point) 166-167 ℃.
1 H NMR(500MHz,DMSO-d 6 )δ12.47(s,1H),11.65(s,1H),8.26(s,1H),7.73(d,J ＝8.1Hz,1H),7.66(dd,J＝8.4,0.5Hz,1H),7.44(d,J＝0.9Hz,1H),7.35-7.29(m, 1H),7.13-7.07(m,1H),3.77(s,3H),2.20(ddd,J＝14.1,11.7,4.5Hz,1H),2.05(ddd, J＝14.0,11.6,4.8Hz,1H),1.31-1.23(m,1H),1.20-1.12(m,4H),1.11-1.01(m,1H), 0.75(t,J＝6.9Hz,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ167.94,159.26,158.10, 137.97,127.33,126.92,126.31,122.34,120.75,112.90,112.83,112.81,107.29, 63.61,39.52,30.84,22.36,21.81,13.73；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 23 N 2 O 5 359.1601；Found 359.1600.
Compound two (4 ab):
4- (4-fluoro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(4-fluoro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxa mide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (65.6 mg, 70% yield), mp 178-179 ℃.
1 H NMR(500MHz,DMSO-d 6 )δ12.58(s,1H),11.71(s,1H),8.33(s,1H),7.54(d,J ＝8.4Hz,1H),7.38(d,J＝1.1Hz,1H),7.34-7.26(m,1H),6.90(dd,J＝10.4,7.8Hz, 1H),3.77(s,3H),2.20(ddd,J＝14.1,11.6,4.5Hz,1H),2.04(ddd,J＝14.0,11.5,4.8 Hz,1H),1.33-1.24(m,1H),1.22-1.15(m,4H),1.13-1.04(m,1H),0.76(t,J＝6.9Hz, 3H)； 13 C NMR(125MHz,DMSO-d 6 )δ167.56,158.88,157.20,155.98(d,J C-F ＝ 248.7Hz),139.99(d,J C-F ＝9.6Hz),127.14,126.57(d,J C-F ＝7.6Hz),116.88(d,J C-F ＝22.4Hz),114.52,109.61(d,J C-F ＝3.5Hz),107.24,107.06,104.72(d,J C-F ＝17.8 Hz),63.57,39.11,30.76,22.32,21.77,13.68；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 FN 2 O 5 377.1507；Found 377.1506.
Compound three (4 ac):
4- (4-chloro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(4-chloro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amid
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (64.8 mg, 66% yield), mp 162-163 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.57(s,1H),11.75(s,1H),8.40(s,1H),7.69(d,J ＝8.3Hz,1H),7.35(s,1H),7.32-7.27(m,1H),7.20(d,J＝7.5Hz,1H),3.77(s,3H), 2.24-2.14(m,1H),2.07-1.97(m,1H),1.32-1.25(m,1H),1.20-1.14(m,4H), 1.12-1.03(m,1H),0.75(t,J＝6.8Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.54, 158.86,156.98,138.49,127.51,126.59,125.96,125.80,120.26,115.07,112.33, 109.20,107.26,63.60,39.14,30.82,22.37,21.83,13.74；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 ClN 2 O 5 393.1212；Found 393.1209.
Compound four (4 ad):
4- (4-bromo-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(4-bromo-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (43.5 mg, 40% yield), mp 146-147 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.56(s,1H),11.75(s,1H),8.40(s,1H),7.73(d,J ＝8.3Hz,1H),7.36(d,J＝7.5Hz,1H),7.28(s,1H),7.26-7.22(m,1H),3.78(s,3H), 2.24-2.15(m,1H),2.04-1.98(m,1H),1.31-1.25(m,1H),1.20-1.13(m,4H), 1.12-1.04(m,1H),0.76(t,J＝6.6Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.49, 158.81,156.83,138.09,127.75,127.36,126.85,123.44,115.18,114.80,112.77, 110.77,107.20,63.57,39.09,30.80,22.34,21.80,13.72；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 BrN 2 O 5 437.0707；Found437.0704.
Compound five (4 ae):
4- (5-fluoro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(5-fluoro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxa mide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (64.2 mg, 68% yield), mp 181-182 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.46(s,1H),11.70(s,1H),8.32(s,1H),7.72(dd, J＝9.0,4.5Hz,1H),7.51(dd,J＝9.4,2.1Hz,1H),7.40(s,1H),7.23-7.15(m,1H), 3.77(s,3H),2.24-2.15(m,1H),2.08-1.99(m,1H),1.30-1.24(m,1H),1.21-1.14(m, 4H),1.11-1.02(m,1H),0.76(t,J＝6.6Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ 167.76,159.05,157.62,157.41(d,J C-F ＝234.9Hz),134.80,128.36,127.32(d,J C-F ＝ 10.8Hz),115.20(d,J C-F ＝27.1Hz),114.54(d,J C-F ＝9.2Hz),113.87,112.24(d,J C-F ＝5.7Hz),107.30,105.99(d,J C-F ＝23.3Hz),63.63,39.30,30.86,22.37,21.84,13.75； HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 FN 2 O 5 377.1507；Found 377.1505.
Compound six (4 af):
4- (5-chloro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(5-chloro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (69.3 mg, 71% yield), mp 141-142 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.49(s,1H),11.71(s,1H),8.33(s,1H),7.82(s, 1H),7.73(d,J＝8.8Hz,1H),7.40(s,1H),7.30(dd,J＝8.8,1.4Hz,1H),3.77(s,3H), 2.23-2.13(m,1H),2.07-1.96(m,1H),1.30-1.25(m,1H),1.19-1.13(m,4H), 1.10-1.03(m,1H),0.75(t,J＝6.3Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.66, 158.93,157.44,136.29,128.19,128.12,126.06,125.19,121.12,114.76,114.30, 111.68,107.28,63.61,39.20,30.83,22.34,21.81,13.74；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 ClN 2 O 5 393.1212；Found 393.1207.
Compound seven (4 ag):
4- (5-bromo-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(5-bromo-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (71.6 mg, 66% yield), mp 145-146 ℃.
1 H NMR(500MHz,DMSO-d 6 )δ12.48(s,1H),11.69(s,1H),8.31(s,1H),7.97(d,J ＝1.7Hz,1H),7.68(d,J＝8.8Hz,1H),7.44-7.36(m,2H),3.77(s,3H),2.24-2.13(m, 1H),2.07-1.97(m,1H),1.33-1.24(m,1H),1.21-1.13(m,4H),1.11-1.02(m,1H), 0.76(t,J＝6.8Hz,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ167.63,158.90,157.38, 136.46,128.91,128.46,127.92,124.26,115.10,114.36,113.15,111.51,107.26,63.59, 39.16,30.80,22.30,21.78,13.71；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 BrN 2 O 5 437.0707；Found 437.0709.
Compound eight (4 ah):
5-hydroxy-4- (5-iodo-1H-indol-2-yl) -N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-4-(5-iodo-1H-indol-2-yl)-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxa mide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (79.5 mg, 66% yield), mp 135-136 ℃.
1 H NMR(500MHz,DMSO-d 6 )δ12.45(s,1H),11.67(s,1H),8.28(s,1H),8.14(s, 1H),7.57-7.49(m,2H),7.35(d,J＝1.6Hz,1H),3.75(s,3H),2.22-2.10(m,1H), 2.06-1.93(m,1H),1.29-1.21(m,1H),1.19-1.10(m,4H),1.09-1.00(m,1H),0.74(t,J ＝6.7Hz,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ167.66,158.93,157.40,136.76, 133.78,130.61,129.85,127.45,115.36,114.22,111.22,107.26,84.67,63.59,39.18, 30.80,22.30,21.77,13.72；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 IN 2 O 5 485.0568；Found 485.0567.
Compound nine (4 ai):
4- (6-fluoro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(6-fluoro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxa mide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (67.1 mg, 71% yield), mp 150-151 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.53(s,1H),11.67(s,1H),8.28(s,1H),7.78(dd, J＝8.7,5.6Hz,1H),7.55(d,J＝9.9Hz,1H),7.47(s,1H),7.02-6.96(m,1H),3.77(s, 3H),2.24-2.14(m,1H),2.08-1.99(m,1H),1.30-1.23(m,1H),1.20-1.13(m,4H), 1.10-1.03(m,1H),0.76(t,J＝6.6Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.88, 161.48(d,J C-F ＝241.2Hz),159.20,157.74,138.18(d,J C-F ＝13.6Hz),127.72(d,J C-F ＝3.2Hz),124.34,124.13(d,J C-F ＝10.4Hz),113.20,112.72,110.38(d,J C-F ＝25.7 Hz),107.23,98.62(d,J C-F ＝26.4Hz),63.61,39.48,30.83,22.36,21.81,13.73； HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 FN 2 O 5 377.1507；Found 377.1506.
Compound ten (4 aj):
4- (6-chloro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(6-chloro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (72.9 mg, 74% yield), mp 183-184 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.44(s,1H),11.69(s,1H),8.31(s,1H),7.84(s, 1H),7.76(d,J＝8.6Hz,1H),7.45(s,1H),7.12(dd,J＝8.6,1.6Hz,1H),3.77(s,3H), 2.22-2.15(m,1H),2.06-1.98(m,1H),1.30-1.24(m,1H),1.20-1.13(m,4H), 1.11-1.04(m,1H),0.76(t,J＝6.6Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.71, 158.99,157.47,138.16,130.69,127.78,125.99,123.77,121.36,113.79,112.63, 107.26,63.60,39.26,30.82,22.34,21.80,13.73；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 ClN 2 O 5 393.1212；Found 393.1212.
Compound eleven (4 ak):
4- (6-bromo-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(6-bromo-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (81.5 mg, 75% yield), mp 191-192 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.41(s,1H),11.69(s,1H),8.33(s,1H),7.98(s, 1H),7.70(d,J＝8.6Hz,1H),7.43(s,1H),7.23(d,J＝8.5Hz,1H),3.77(s,3H), 2.22-2.14(m,1H),2.07-1.98(m,1H),1.28-1.24(m,1H),1.19-1.13(m,4H), 1.10-1.03(m,1H),0.75(t,J＝6.4Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.76, 159.02,157.47,138.59,127.64,126.22,124.04,123.90,119.16,115.71,113.99, 112.63,107.33,63.66,39.26,30.85,22.38,21.84,13.77；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 BrN 2 O 5 437.0707；Found437.0706.
Compound twelve (4 al):
4- (7-fluoro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(7-fluoro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxa mide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (61.8 mg, 66% yield), mp 188-189 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.94(s,1H),11.20(s,1H),7.53(s,1H),7.37(d,J＝ 7.5Hz,1H),6.97-6.85(m,2H),5.36(s,1H),3.89(s,3H),2.40-2.29(m,1H), 2.10-2.00(m,1H),1.36-1.28(m,1H),1.23-1.14(m,4H),1.13-1.05(m,1H),0.79(t,J ＝6.6Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.64,160.62,160.12,149.59(d,J C-F ＝248.8Hz),130.98(d,J C-F ＝4.4Hz),128.12(d,J C-F ＝14.1Hz),127.40,121.37(d, J C-F ＝5.4Hz),118.42(d,J C-F ＝4.0Hz),115.67,111.45(d,J C-F ＝15.6Hz),110.05, 108.04,64.85,41.00,31.46,22.77,22.44,13.99；HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 22 FN 2 O 5 377.1507；Found 377.1507.
Compound thirteen (4 am):
5-hydroxy-N-methoxy-4- (4-methyl-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(4-methyl-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (72.1 mg, 77% yield), mp 184-185 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.82(s,1H),11.12(s,1H),7.48(s,1H),7.24-7.16(m, 2H),6.84(d,J＝6.0Hz,1H),5.22(s,1H),3.86(s,3H),2.51(s,3H),2.37-2.28(m, 1H),2.10-2.03(m,1H),1.34-1.27(m,1H),1.22-1.14(m,4H),1.12-1.05(m,1H), 0.79(t,J＝6.8Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.87,161.06,159.95, 139.22,132.74,128.49,128.35,126.40,121.22,114.47,110.38,108.51,107.87, 64.76,41.37,31.48,22.82,22.46,18.89,14.00；HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 5 373.1758；Found 373.1757.
Compound fourteen (4 an):
5-hydroxy-N-methoxy-4- (4-methoxy-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(4-methoxy-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carb oxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give an orange amorphous solid (87.1 mg, 90% yield), mp 147-148 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.90(s,1H),11.17(s,1H),7.53(s,1H),7.25-7.19(m, 1H),6.97(d,J＝8.3Hz,1H),6.36(d,J＝7.7Hz,1H),4.94(s,1H),3.92(s,3H),3.88 (s,3H),2.34-2.28(m,1H),2.08-2.00(m,1H),1.33-1.29(m,1H),1.22-1.14(m,4H), 1.13-1.06(m,1H),0.79(t,J＝6.8Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ170.04, 160.86,159.65,154.37,140.47,129.15,126.03,120.21,113.29,108.47,107.79, 105.94,99.57,64.78,55.48,41.27,31.49,22.87,22.50,14.02；HRMS(ESI)m/z:[M +H] + Calcd for C 20 H 25 N 2 O 6 389.1707；Found 389.1704.
Compound pentadecyl (4 ao):
5-hydroxy-N-methoxy-4- (5-methyl-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(5-methyl-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (65.6 mg, 70% yield), mp 155-156 ℃.
1 H NMR(500MHz,DMSO-d 6 )δ12.44(s,1H),11.63(s,1H),8.23(s,1H),7.56(d,J ＝8.5Hz,1H),7.50(s,1H),7.35(d,J＝0.7Hz,1H),7.17(dd,J＝8.5,1.2Hz,1H), 3.77(s,3H),2.38(s,3H),2.20(ddd,J＝14.0,11.7,4.5Hz,1H),2.04(ddd,J＝14.0, 11.5,4.8Hz,1H),1.31-1.23(m,1H),1.21-1.13(m,4H),1.11-1.01(m,1H),0.76(t,J ＝6.9Hz,3H)； 13 C NMR(125MHz,DMSO-d 6 )δ168.02,159.36,158.25,136.57, 129.55,128.50,127.63,126.92,121.25,112.61,112.35,112.17,107.23,63.58,39.59, 30.80,22.32,21.77,21.07,13.70；HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 5 373.1758；Found 373.1756.
Compound sixteen (4 ap):
5-hydroxy-N-methoxy-4- (5-methoxy-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(5-methoxy-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carb oxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petroleum/ethyl acetate: 8/1. Fwdarw. Petroleum/ethyl acetate: 4/1) to give a yellow viscous oil (69.6 mg, 72% yield).
1 H NMR(600MHz,DMSO-d 6 )δ12.47(s,1H),11.63(s,1H),8.26(s,1H),7.59(d,J ＝9.0Hz,1H),7.35(s,1H),7.18(s,1H),6.99(dd,J＝9.0,2.2Hz,1H),3.77(s,3H), 3.77(s,3H),2.24-2.16(m,1H),2.08-2.01(m,1H),1.28-1.23(m,1H),1.20-1.13(m, 4H),1.10-1.02(m,1H),0.76(t,J＝6.4Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ 168.08,159.41,158.18,154.25,133.72,127.78,127.17,118.60,113.99,112.35, 111.87,107.23,101.51,63.61,55.25,39.63,30.86,22.38,21.83,13.76；HRMS(ESI) m/z:[M+H] + Calcd for C 20 H 25 N 2 O 6 389.1707；Found 389.1706.
Seventeen (4 aq):
4- (5-ethoxy-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(5-ethoxy-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give an orange amorphous solid (69.5 mg, 69% yield), mp 151-152 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.83(s,1H),11.16(s,1H),7.34(s,1H),7.23(d,J＝ 9.0Hz,1H),6.97(dd,J＝9.0,2.3Hz,1H),6.85(d,J＝1.7Hz,1H),5.07(s,1H), 4.01(q,J＝6.9Hz,2H),3.86(s,3H),2.36-2.28(m,1H),2.09-2.00(m,1H),1.44(t,J ＝6.9Hz,3H),1.36-1.29(m,1H),1.23-1.16(m,4H),1.14-1.08(m,1H),0.79(t,J＝ 6.9Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.96,161.05,159.93,154.18,135.20, 128.33,127.14,121.32,114.78,113.85,108.12,107.80,102.24,64.79,63.95,41.21, 31.51,22.81,22.47,15.01,14.02；HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 27 N 2 O 6 403.1864；Found 403.1861.
Compound eighteen (4 ar):
5-hydroxy-N-methoxy-4- (6-methyl-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(6-methyl-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (70.0 mg, 75% yield), mp 169-170 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.64(s,1H),11.17(s,1H),7.49-7.43(m,2H),7.04(s, 1H),6.88(dd,J＝8.3,0.9Hz,1H),5.28(s,1H),3.85(s,3H),2.41(s,3H),2.35-2.27 (m,1H),2.08-2.01(m,1H),1.32-1.28(m,1H),1.21-1.14(m,4H),1.12-1.06(m,1H), 0.78(t,J＝7.0Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ170.01,161.12,159.91, 139.86,138.74,126.58,126.09,123.87,122.34,116.04,112.26,107.92,107.85, 64.73,41.31,31.49,22.79,22.47,22.45,14.01；HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 5 373.1758；Found 373.1754.
Nineteen (4 as):
5-hydroxy-N-methoxy-4- (6-methoxy-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(6-methoxy-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carb oxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (68.5 mg, 71% yield), mp 135-136 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.72(s,1H),11.20(s,1H),7.48-7.40(m,2H),6.70 (dd,J＝8.9,2.1Hz,1H),6.57(d,J＝1.5Hz,1H),5.33(s,1H),3.85(s,3H),3.81(s, 3H),2.31(ddd,J＝14.1,12.1,4.4Hz,1H),2.03(ddd,J＝14.0,12.1,4.4Hz,1H), 1.35-1.30(m,1H),1.22-1.15(m,4H),1.14-1.06(m,1H),0.79(t,J＝6.9Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ170.13,161.48,160.99,159.22,140.98,126.37,123.69, 123.04,116.71,114.78,107.65,106.41,93.12,64.72,55.53,41.46,31.52,22.80, 22.46,14.02；HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 6 389.1707；Found 389.1703.
Compound twenty (4 at):
5-hydroxy-N-methoxy-4- (7-methyl-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(7-methyl-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (23.4 mg, yield 25%), mp 168-169 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.91(s,1H),11.11(s,1H),7.50(d,J＝1.8Hz,1H), 7.44(d,J＝8.1Hz,1H),7.07(d,J＝6.9Hz,1H),7.00-6.95(m,1H),5.30(s,1H), 3.86(s,3H),2.50(s,3H),2.39-2.30(m,1H),2.09-2.03(m,1H),1.34-1.30(m,1H), 1.24-1.15(m,4H),1.13-1.07(m,1H),0.79(t,J＝6.9Hz,3H)； 13 C NMR(150MHz, CDCl 3 )δ169.84,161.10,160.10,139.47,127.80,127.52,126.48,122.52,121.84, 120.22,116.29,108.47,107.86,64.73,41.32,31.51,22.81,22.47,16.81,14.03； HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 5 373.1758；Found 373.1755.
Compound twenty-one (4 au):
5-hydroxy-N-methoxy-4- (7-methoxy-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide 5-hydroxy-N-methoxy-4- (7-methoxy-1H-indol-2-yl) -2-oxo-5-pentayl-2, 5-dihydrofuran-3-carb oxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (65.2 mg, 67% yield), mp 183-184 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.95(s,1H),11.06(s,1H),7.44(d,J＝1.5Hz,1H), 7.17(d,J＝8.2Hz,1H),6.99-6.92(m,1H),6.64(d,J＝7.5Hz,1H),5.06(s,1H), 3.97(s,3H),3.85(s,3H),2.36-2.28(m,1H),2.08-2.02(m,1H),1.33-1.26(m,1H), 1.22-1.12(m,4H),1.11-1.02(m,1H),0.78(t,J＝6.8Hz,3H)； 13 C NMR(150MHz, CDCl 3 )δ169.79,160.63,159.91,146.79,130.94,129.13,126.47,121.88,115.58, 114.78,109.11,107.77,105.78,64.76,55.63,41.15,31.48,22.79,22.45,14.00； HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 6 389.1707；Found 389.1706.
Compound twenty-two (4 av):
4- (5- (furan-2-yl) -1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(5-(furan-2-yl)-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-ca rboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give an orange amorphous solid (49.0 mg, 46% yield), mp 153-154 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.84(s,1H),11.22(s,1H),7.84(s,1H),7.52(dd,J＝ 8.7,1.4Hz,1H),7.48(s,1H),7.45(d,J＝1.4Hz,1H),7.26-7.24(m,1H),6.53(d,J ＝3.3Hz,1H),6.46(dd,J＝3.2,1.7Hz,1H),5.05(s,1H),3.89(s,3H),2.39-2.31(m, 1H),2.10-2.03(m,1H),1.40-1.31(m,1H),1.24-1.17(m,4H),1.17-1.10(m,1H), 0.79(t,J＝6.9Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.79,160.92,159.90, 154.43,141.83,138.56,128.00,127.49,125.16,124.74,117.13,115.83,113.13, 111.80,107.91,104.35,64.81,41.12,31.48,22.79,22.44,13.99；HRMS(ESI)m/z: [M-H] - Calcd for C 23 H 23 N 2 O 6 423.1562；Found 423.1564.
Compound twenty-three (4 aw):
5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-4- (5- (thiophen-2-yl) -1H-indol-2-yl) -2,5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-2-oxo-5-pentyl-4-(5-(thiophen-2-yl)-1H-indol-2-yl)-2,5-dihydrofuran-3 -carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give an orange amorphous solid (77.7 mg, 71% yield), mp 134-135 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.85(s,1H),11.23(s,1H),7.79(s,1H),7.53-7.46(m, 2H),7.26-7.24(m,1H),7.24(s,1H),7.20-7.17(m,1H),7.05(dd,J＝5.0,3.6Hz, 1H),5.04(s,1H),3.89(s,3H),2.39-2.32(m,1H),2.12-2.04(m,1H),1.39-1.32(m, 1H),1.24-1.16(m,4H),1.16-1.09(m,1H),0.80(t,J＝7.0Hz,3H)； 13 C NMR(150 MHz,CDCl 3 )δ169.77,160.88,159.94,144.95,138.63,128.21,128.15,127.61, 127.07,124.32,122.77,119.20,115.69,113.21,107.93,64.83,41.14,31.49,22.81, 22.46,14.01；HRMS(ESI)m/z:[M-H] - Calcd for C 23 H 23 N 2 O 5 S 439.1333；Found 439.1336.
Chemical combinationTwenty-four (4 ax):
4- (5-cyano-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(5-cyano-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxa mide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 4/1. Fwdarw. Petrol/ethyl acetate: 2/1) to give a yellow amorphous solid (63.3 mg, 66% yield), mp 204-205 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.62(s,1H),11.75(s,1H),8.38(s,1H),8.34(s, 1H),7.88(d,J＝8.6Hz,1H),7.62(dd,J＝8.7,1.3Hz,1H),7.51(s,1H),3.77(s,3H), 2.23-2.13(m,1H),2.05-1.97(m,1H),1.31-1.27(m,1H),1.19-1.14(m,4H), 1.11-1.04(m,1H),0.76(t,J＝6.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.36, 158.60,156.70,139.06,128.89,128.42,127.42,126.74,120.04,115.77,114.49, 112.35,107.28,102.88,63.60,38.88,30.81,22.31,21.79,13.73；HRMS(ESI)m/z: [M+H] + Calcd for C 20 H 22 N 3 O 5 384.1554；Found 384.1552.
Compound twenty-five (4 ay):
methyl 2- (2-hydroxy-4- (methoxycarbamoyl) -5-carbonyl-2-pentyl-2, 5-dihydrofuran-3-yl) -1H-indole-5-carboxylic acid ester
methyl2-(2-hydroxy-4-(methoxycarbamoyl)-5-oxo-2-pentyl-2,5-dihydrofuran-3-yl)-1H-indole -5-carboxylate
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (75.1 mg, 72% yield), mp 141-142 ℃.
1 H NMR(600MHz,CDCl 3 )δ13.01(s,1H),11.28(s,1H),8.14(s,1H),7.80(dd,J＝ 8.8,1.2Hz,1H),7.47(s,1H),7.25(d,J＝8.2Hz,1H),5.68(s,1H),3.91(s,3H), 3.88(s,3H),2.35(ddd,J＝14.2,12.0,4.4Hz,1H),2.04(ddd,J＝14.0,12.1,4.4Hz, 1H),1.41-1.33(m,1H),1.24-1.16(m,4H),1.15-1.08(m,1H),0.79(t,J＝6.9Hz, 3H)； 13 C NMR(150MHz,CDCl 3 )δ169.67,168.21,160.53,160.02,140.60,128.28, 127.80,127.01,126.24,122.62,116.49,112.37,110.37,108.08,64.85,52.41,40.87, 31.47,22.77,22.44,13.99；HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 25 N 2 O 7 417.1656；Found 417.1650.
Compound twenty-six (4 az):
5-hydroxy-N-methoxy-4- (3-methyl-1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(3-methyl-1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 4/1. Fwdarw. Petrol/ethyl acetate: 2/1) to give a yellow amorphous solid (15.5 mg, 17% yield), mp 137-138 ℃.
1 H NMR(600MHz,CDCl 3 )δ10.80(s,1H),10.56(s,1H),7.57(d,J＝8.1Hz,1H), 7.30-7.26(m,1H),7.19(d,J＝8.3Hz,1H),7.13-7.06(m,1H),6.33(s,1H),3.86(s, 3H),2.36(s,3H),1.98(ddd,J＝15.7,11.6,4.5Hz,1H),1.65(ddd,J＝14.0,11.9,4.0 Hz,1H),1.31-1.27(m,1H),1.16-1.02(m,5H),0.74(t,J＝7.1Hz,3H)； 13 C NMR (150MHz,CDCl 3 )δ169.85,161.09,160.57,138.24,128.87,126.95,124.04,123.92, 120.84,120.38,112.14,111.76,107.80,64.92,37.48,31.34,22.39,22.36,13.89, 12.36；HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 5 373.1758；Found 373.1761.
Twenty-seven (4 ba) compounds:
4- (3-benzyl-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
4-(3-benzyl-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-pentyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 4/1. Fwdarw. Petrol/ethyl acetate 2/1) to give a yellow amorphous solid (32.9 mg, 29% yield), mp 115-116 ℃.
1 H NMR(600MHz,CDCl 3 )δ10.77(s,1H),10.61(s,1H),7.31(d,J＝8.2Hz,1H), 7.25-7.21(m,2H),7.19-7.15(m,2H),7.14-7.10(m,1H),7.02-6.94(m,3H),6.17(s, 1H),4.38(d,J＝16.8Hz,1H),4.09(d,J＝16.8Hz,1H),3.86(s,3H),1.91-1.82(m, 1H),1.55-1.48(m,1H),1.23-1.18(m,1H),1.09-1.03(m,2H),1.01-0.92(m,3H), 0.73(t,J＝7.3Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.59,161.28,160.46, 140.44,138.32,128.56,128.45,128.41,126.70,126.15,125.28,124.30,121.70, 120.61,112.84,112.16,107.88,64.96,37.54,32.54,31.37,22.39,22.32,14.00； HRMS(ESI)m/z:[M+H] + Calcd for C 26 H 29 N 2 O 5 449.2071；Found 449.2069.
Compound twenty-eight (4 bb):
n-ethoxy-5-hydroxy-4- (1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
N-ethoxy-5-hydroxy-4-(1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (72.7 mg, 78% yield), mp 152-153 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.89(s,1H),11.07(s,1H),7.60(d,J＝8.1Hz,1H), 7.49(s,1H),7.36(d,J＝8.3Hz,1H),7.32-7.28(m,1H),7.11-7.05(m,1H),5.05(s, 1H),4.12-3.98(m,2H),2.38-2.29(m,1H),2.11-2.00(m,1H),1.37-1.29(m,4H), 1.23-1.15(m,4H),1.15-1.08(m,1H),0.79(t,J＝6.9Hz,3H)； 13 C NMR(150MHz, CDCl 3 )δ169.91,160.86,159.93,139.15,127.90,127.87,126.93,122.81,121.38, 115.68,112.94,109.26,107.88,72.84,41.19,31.48,22.80,22.45,14.01,13.56； HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 25 N 2 O 5 373.1758；Found 373.1759.
Compound twenty-nine (4 bc):
5-hydroxy-4- (1H-indol-2-yl) -N-isopropoxy-2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-4- (1H-indol-2-yl) -N-isopropoxy-2-oxo-5-pental-2, 5-dihydroofuran-3-carboxamide the reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (74.0 mg, 77% yield), mp 134-135 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.93(s,1H),10.98(s,1H),7.59(d,J＝8.1Hz,1H), 7.48(s,1H),7.37(d,J＝8.4Hz,1H),7.33-7.27(m,1H),7.11-7.04(m,1H),4.97(s, 1H),4.26-4.18(m,1H),2.33(ddd,J＝16.1,11.8,4.5Hz,1H),2.05(ddd,J＝13.9, 12.1,4.2Hz,1H),1.35-1.28(m,7H),1.23-1.11(m,5H),0.79(t,J＝6.9Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.97,160.90,159.76,139.13,127.90,127.77,126.99, 122.79,121.32,115.58,112.97,109.44,107.84,79.06,41.18,31.49,22.80,22.46, 20.67,20.62,14.01；HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 27 N 2 O 5 387.1914； Found 387.1913.
Compound thirty (4 bd):
n- (tert-butoxy) -5-hydroxy-4- (1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
N-(tert-butoxy)-5-hydroxy-4-(1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (50.4 mg, yield 50%), mp 139-140 ℃.
1 H NMR(600MHz,CDCl 3 )δ13.07(s,1H),10.82(s,1H),7.62(d,J＝8.2Hz,1H), 7.49(s,1H),7.42(d,J＝8.4Hz,1H),7.35-7.29(m,1H),7.12-7.06(m,1H),4.90(s, 1H),2.39-2.30(m,1H),2.11-2.03(m,1H),1.40-1.31(m,10H),1.23-1.11(m,5H), 0.80(t,J＝6.3Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ170.17,161.12,159.60, 139.14,127.92,127.67,127.07,122.77,121.27,115.47,113.06,109.69,107.82, 83.55,41.17,31.49,26.36,22.82,22.47,14.01；HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 29 N 2 O 5 401.2071；Found 401.2069.
Compound thirty-one (4 be):
n- (benzyloxy) -5-hydroxy-4- (1H-indol-2-yl) -2-carbonyl-5-pentyl-2, 5-dihydrofuran-3-carboxamide
N-(benzyloxy)-5-hydroxy-4-(1H-indol-2-yl)-2-oxo-5-pentyl-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (77.8 mg, 72% yield), mp 129-130 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.88(s,1H),11.05(s,1H),7.61(d,J＝8.1Hz,1H), 7.50(s,1H),7.46-7.34(m,6H),7.34-7.29(m,1H),7.12-7.07(m,1H),5.04-4.92(m, 2H),2.32(ddd,J＝14.1,11.9,4.4Hz,1H),2.05(ddd,J＝13.9,12.0,4.4Hz,1H), 1.35-1.29(m,1H),1.23-1.14(m,4H),1.14-1.07(m,1H),0.80(t,J＝6.9Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.71,160.78,159.88,139.18,134.53,129.26,129.16, 128.85,127.92,126.92,122.84,121.43,115.69,112.99,109.28,107.84,78.84,41.19, 31.47,22.80,22.47,14.00；HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 27 N 2 O 5 435.1914；Found 435.1911.
Compound thirty-two (4 bf):
5-ethyl-5-hydroxy-4- (1H-indol-2-yl) -N-methoxy-2-carbonyl-2, 5-dihydrofuran-3-carboxamide
5-ethyl-5-hydroxy-4-(1H-indol-2-yl)-N-methoxy-2-oxo-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (54.7 mg, 69% yield), mp 175-176 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.48(s,1H),11.69(s,1H),8.30(s,1H),7.74(d,J ＝8.1Hz,1H),7.67(d,J＝8.4Hz,1H),7.44(s,1H),7.35-7.31(m,1H),7.14-7.09(m, 1H),3.78(s,3H),2.30-2.20(m,1H),2.14-2.05(m,1H),0.76(t,J＝7.4Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.97,159.25,157.80,137.97,127.33,126.87, 126.32,122.31,120.77,113.05,112.90,112.85,107.68,63.61,32.78,7.45；HRMS (ESI)m/z:[M+H] + Calcd for C 16 H 17 N 2 O 5 317.1132；Found 317.1133.
Compound thirty-three (4 bg):
5-butyl-5-hydroxy-4- (1H-indol-2-yl) -N-methoxy-2-carbonyl-2, 5-dihydrofuran-3-carboxamide
5-butyl-5-hydroxy-4-(1H-indol-2-yl)-N-methoxy-2-oxo-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (52.8 mg, 61% yield), mp 166-167 ℃.
1 H NMR(600MHz,CDCl 3 )δ12.85(s,1H),11.11(s,1H),7.61(d,J＝8.1Hz,1H), 7.51(s,1H),7.36(d,J＝8.4Hz,1H),7.32-7.28(m,1H),7.10-7.05(m,1H),5.31(s, 1H),3.84(s,3H),2.39-2.28(m,1H),2.12-2.02(m,1H),1.32-1.21(m,3H),1.13-1.03 (m,1H),0.79(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ169.89,160.87, 160.09,139.16,127.96,127.88,126.88,122.83,121.44,115.79,112.91,109.06, 107.98,64.75,40.97,25.16,22.45,13.87；HRMS(ESI)m/z:[M+H] + Calcd for C 18 H 21 N 2 O 5 345.1445；Found 345.1443.
Compound thirty-four (4 bh):
5-benzyl-5-hydroxy-4- (1H-indol-2-yl) -N-methoxy-2-carbonyl-2, 5-dihydrofuran-3-carboxamide
5-benzyl-5-hydroxy-4-(1H-indol-2-yl)-N-methoxy-2-oxo-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petroleum/ethyl acetate: 8/1. Fwdarw. Petroleum/ethyl acetate: 4/1) to give a yellow viscous oil (33.8 mg, 36% yield).
1 H NMR(600MHz,DMSO-d 6 )δ12.62(s,1H),11.44(s,1H),8.53(s,1H),7.81(d,J ＝8.1Hz,1H),7.70(d,J＝8.4Hz,1H),7.67(s,1H),7.39-7.34(m,1H),7.20-7.13(m, 4H),6.96-6.90(m,2H),3.68(s,3H),3.54(d,J＝13.7Hz,1H),3.45(d,J＝13.8Hz, 1H)； 13 C NMR(150MHz,DMSO-d 6 )δ167.62,158.94,158.05,137.99,133.77, 130.13,127.96,127.50,127.29,127.05,126.52,122.52,120.85,113.63,112.98, 112.71,106.67,63.53,45.73；HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 19 N 2 O 5 379.1288；Found 379.1290.
Compound thirty-five (4 bi):
5-hydroxy-4- (1H-indol-2-yl) -N-methoxy-2-carbonyl-5-phenyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-4-(1H-indol-2-yl)-N-methoxy-2-oxo-5-phenyl-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (59.8 mg, 66% yield), mp 214-215 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.41(s,1H),11.80(s,1H),9.08(s,1H),7.65-7.60 (m,3H),7.58(d,J＝8.1Hz,1H),7.43-7.39(m,2H),7.39-7.35(m,1H),7.29-7.25(m, 1H),7.05-7.01(m,1H),6.99(s,1H),3.83(s,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ 168.28,159.25,157.84,138.75,137.76,129.28,128.62,127.06,126.90,126.35, 125.33,122.18,120.75,113.60,112.99,112.87,105.45,63.69；HRMS(ESI)m/z:[M +H] + Calcd for C 20 H 17 N 2 O 5 365.1132；Found 365.1133.
Compound thirty-six (4 bj):
4- (4-fluoro-1H-indol-2-yl) -5-hydroxy-N-methoxy-2-carbonyl-5-phenyl-2, 5-dihydrofuran-3-carboxamide
4-(4-fluoro-1H-indol-2-yl)-5-hydroxy-N-methoxy-2-oxo-5-phenyl-2,5-dihydrofuran-3-carbox amide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 4/1. Fwdarw. Petrol/ethyl acetate: 2/1) to give a yellow amorphous solid (64.6 mg, 68% yield), mp 236-237 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.54(s,1H),11.85(s,1H),9.14(s,1H),7.63(d,J ＝7.7Hz,2H),7.50(d,J＝8.4Hz,1H),7.44-7.36(m,3H),7.27-7.21(m,1H),6.93(s, 1H),6.82(dd,J＝10.3,7.9Hz,1H),3.83(s,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ 167.96,158.89,157.00,155.78(d,J C-F ＝248.7Hz),139.76(d,J＝9.6Hz),138.34, 129.41,128.68,127.14,126.65(d,J C-F ＝7.5Hz),125.35,116.66(d,J C-F ＝22.2Hz), 114.57,109.62(d,J C-F ＝3.6Hz),107.79,105.40,104.70(d,J C-F ＝18.0Hz),63.67； HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 16 FN 2 O 5 383.1038；Found 383.1037.
Compound thirty-seven (4 bk):
5-hydroxy-N-methoxy-4- (4-methyl-1H-indol-2-yl) -2-carbonyl-5-phenyl-2, 5-dihydrofuran-3-carboxamide
5-hydroxy-N-methoxy-4-(4-methyl-1H-indol-2-yl)-2-oxo-5-phenyl-2,5-dihydrofuran-3-carbo xamide
The reaction mixture was purified by flash chromatography directly on silica gel (petroleum/ethyl acetate: 8/1. Fwdarw. Petroleum/ethyl acetate: 4/1) to give a yellow viscous oil (77.2 mg, 82% yield).
1 H NMR(600MHz,DMSO-d 6 )δ12.40(s,1H),11.79(s,1H),9.09(s,1H),7.63(d,J ＝7.6Hz,2H),7.45-7.39(m,3H),7.39-7.35(m,1H),7.19-7.14(m,1H),7.00(s,1H), 6.82(d,J＝6.9Hz,1H),3.83(s,3H),2.34(s,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ 168.36,159.31,157.84,138.79,137.66,131.05,129.25,128.56,127.43,126.58, 126.40,125.30,120.51,112.63,111.91,110.45,105.40,63.65,18.19；HRMS(ESI) m/z:[M+H] + Calcd for C 21 H 19 N 2 O 5 379.1288；Found 379.1290.
Compound thirty-eight (4 bl):
methyl 2- (2-hydroxy-4- (methoxycarbamoyl) -5-carbonyl-2-phenyl-2, 5-dihydrofuran-3-yl) -1H-indole-5-carboxylic acid ester
methyl2-(2-hydroxy-4-(methoxycarbamoyl)-5-oxo-2-phenyl-2,5-dihydrofuran-3-yl)-1H-indol e-5-carboxylate
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 4/1. Fwdarw. Petrol/ethyl acetate: 2/1) to give a yellow amorphous solid (53.7 mg, 51% yield), mp 234-235 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.49(s,1H),11.86(s,1H),9.15(s,1H),8.31(s, 1H),7.82(d,J＝8.4Hz,1H),7.73(d,J＝8.7Hz,1H),7.63(d,J＝7.4Hz,2H), 7.44-7.33(m,3H),7.18(s,1H),3.83(s,3H),3.82(s,3H)； 13 C NMR(150MHz, DMSO-d 6 )δ167.99,166.61,158.84,157.05,139.77,138.29,129.34,128.62,128.39, 126.57,126.01,125.47,125.04,122.14,114.74,114.28,113.07,105.52,63.69,51.91； HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 19 N 2 O 7 423.1187；Found 423.1185.
Compound thirty-nine (4 bm):
5-hydroxy-4- (1H-indol-2-yl) -N-methoxy-2-carbonyl-5- (p-benzyl) -2,5-dihydrofuran-3-carboxamide
5-hydroxy-4-(1H-indol-2-yl)-N-methoxy-2-oxo-5-(p-tolyl)-2,5-dihydrofuran-3-carboxamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (66.5 mg, 70% yield), mp 242-243 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.40(s,1H),11.78(s,1H),9.00(s,1H),7.62(d,J ＝8.4Hz,1H),7.58(d,J＝8.1Hz,1H),7.49(d,J＝8.2Hz,2H),7.29-7.25(m,1H), 7.20(d,J＝8.2Hz,2H),7.05-7.01(m,1H),6.99(s,1H),3.82(s,3H),2.27(s,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ168.79,159.75,158.41,139.18,138.18,136.35, 129.59,127.50,127.39,126.76,125.73,122.62,121.18,114.04,113.31,106.03, 64.12,21.16；HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 19 N 2 O 5 379.1288；Found 379.1286.
Compound forty (4 bn):
5- (4-chlorophenyl) -5-hydroxy-4- (1H-indol-2-yl) -N-methoxy-2-carbonyl-2, 5-dihydrofuran-3-carboxamide
5-(4-chlorophenyl)-5-hydroxy-4-(1H-indol-2-yl)-N-methoxy-2-oxo-2,5-dihydrofuran-3-carbo xamide
The reaction mixture was purified by flash chromatography directly on silica gel (petrol/ethyl acetate: 8/1. Fwdarw. Petrol/ethyl acetate: 4/1) to give a yellow amorphous solid (59.9 mg, 60% yield), mp 248-249 ℃.
1 H NMR(600MHz,DMSO-d 6 )δ12.40(s,1H),11.79(s,1H),9.19(s,1H),7.67-7.62 (m,3H),7.59(d,J＝8.1Hz,1H),7.47(d,J＝8.7Hz,2H),7.31-7.25(m,1H), 7.07-7.00(m,1H),6.97(s,1H),3.83(s,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ 168.11,159.17,157.34,137.85,137.83,134.05,128.71,127.46,127.11,126.75, 126.45,122.24,120.82,113.59,113.17,112.91,104.89,63.71；HRMS(ESI)m/z:[M +H] + Calcd for C 20 H 16 ClN 2 O 5 399.0742；Found 399.0745。
Claims (9)
1. A method for preparing a compound with a 5-hydroxyfuran-2 (5H) -one skeleton, which is characterized in that the structural formula of the compound with the 5-hydroxyfuran-2 (5H) -one skeleton is shown as a formula < IV >, and the preparation method comprises the following steps:
by means of<Ⅰ>Indole compounds and formula<Ⅱ>The 4-hydroxy-2-alkynoate compound is taken as a substrate and [ Cp ] RhCl is taken as a substrate 2 ] 2 The catalyst, sodium acetate as additive and acetone as solvent react in air atmosphere to obtain the compound<Ⅳ>A compound shown in the specification;
wherein R is 1 Represents a substituent at any position on the phenyl ring selected from the following groups: hydrogen, halogen, alkyl, alkoxy, 3-6 membered heterocyclic ring containing one N, O or S atom, cyano, ester group;
R 2 selected from the following groups: hydrogen, substituted or unsubstituted alkyl;
R 3 selected from the following groups: substituted or unsubstituted alkyl;
R 4 selected from the following groups: substituted or unsubstituted alkyl, aryl;
R 5 selected from the following groups: an alkyl group;
the substitution means that one or more hydrogen atoms on the group are substituted with any group selected from the group consisting of: phenyl.
2. The method of claim 1, wherein the halogen is F, cl, br or I.
3. The method according to claim 1, wherein the alkyl group is methyl, ethyl, isopropyl, n-butyl, t-butyl or n-pentyl; the alkoxy is methoxy or ethoxy; the substituted alkyl is benzyl; the aryl is phenyl, p-methyl substituted phenyl or p-chloro substituted phenyl.
4. The process according to claim 1, wherein the 3-6 membered heterocyclic ring containing one N, O or S atom is the following group:
5. the method according to claim 1, wherein the reaction conditions are: the reaction temperature is 25 ℃, and the reaction time is 5-24h.
6. The process according to claim 1, wherein the molar ratio of compound I to compound II is 1:1.3.
7. The preparation method according to claim 1, wherein the catalyst is used in an amount of 1 to 10% of the molar amount of the compound I.
8. The process of claim 7, wherein the catalyst is used in an amount of 5% of the molar amount of compound I.
9. The process of claim 1, wherein the molar ratio of additive to compound i is 1:1.
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