CN116023357A - New method for converting o-hydroxyacetophenone into quaternary carbon center-containing chromanone compound - Google Patents
New method for converting o-hydroxyacetophenone into quaternary carbon center-containing chromanone compound Download PDFInfo
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- CN116023357A CN116023357A CN202211360442.8A CN202211360442A CN116023357A CN 116023357 A CN116023357 A CN 116023357A CN 202211360442 A CN202211360442 A CN 202211360442A CN 116023357 A CN116023357 A CN 116023357A
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- hydroxyacetophenone
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- -1 chromanone compound Chemical class 0.000 title claims abstract description 28
- JECYUBVRTQDVAT-UHFFFAOYSA-N 2-acetylphenol Chemical compound CC(=O)C1=CC=CC=C1O JECYUBVRTQDVAT-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000000654 additive Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000001632 sodium acetate Substances 0.000 claims abstract description 7
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- 239000012074 organic phase Substances 0.000 claims description 10
- 230000000996 additive effect Effects 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 229960005181 morphine Drugs 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 claims 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 abstract description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 6
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical class C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052789 astatine Inorganic materials 0.000 description 1
- RYXHOMYVWAEKHL-UHFFFAOYSA-N astatine atom Chemical compound [At] RYXHOMYVWAEKHL-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- NQUWWUVODYFMSD-UHFFFAOYSA-N cyanosulfamic acid Chemical compound OS(=O)(=O)NC#N NQUWWUVODYFMSD-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method for obtaining chromanone compounds containing quaternary carbon centers by directly reacting o-hydroxyacetophenone with dimethyl sulfoxide (DMSO) under the promotion of protonic acid, belonging to the technical field of organic synthesis. O-hydroxyacetophenone is used as a raw material, sodium acetate and morpholine are used as additives, dimethyl sulfoxide is heated and activated under an acidic condition to provide diversified synthon reactions, and the chromanone compound with the quaternary carbon center at the 3-position is obtained. The reaction does not need any metal catalyst, is simple to operate, has good reaction selectivity, has a good substrate application range, and has potential industrial application prospect.
Description
Technical Field
The invention relates to a novel synthesis method for converting o-hydroxyacetophenone into a quaternary carbon center-containing chromanone compound, belonging to the technical field of organic synthesis.
Background
The 3-substituted chromanone compound is an important organic intermediate, widely exists in natural products and molecular frameworks with biological and pharmaceutical activities, and attracts more attention in the fields of organic chemistry, pharmaceutical chemistry and the like. In view of this, a series of synthetic methods for synthesizing such compounds have been developed successively from simple raw materials. Among them, the most common is to obtain substituted chromanone compounds from o-hydroxybenzaldehyde through various cyclization reactions. More recent examples of reactions involving activation of o-hydroxyacetophenone and dimethyl sulfoxide (DMSO) have also been presented, such as the 3-substituted chromanones obtained by the DMSO supply of a bissynthon with o-hydroxyacetophenone under oxidising or acidic activation conditions
(reaction 1, chem. Commun.,2017, 53, 5346-5349 and reaction 2, svnthesis 2022, 54, 2185-2192) are more studied. However, the reaction of DMSO activation and formation of the chromanone compound having a quaternary carbon center at the 3-position is not reported, and it is possible that the reaction product of two molecules of DMSO with the reaction continues to react with the third molecule of DMSO with a large steric hindrance, and it is difficult to obtain a molecule having a quaternary carbon center.
Disclosure of Invention
Aiming at the technical problems, the invention provides a novel synthesis method for preparing the chromanone compound with the quaternary carbon center at the 3-position by directly activating dimethyl sulfoxide with acetic acid under the conditions of simple raw material sources and no metal catalysis and providing three different synthesis units to participate in the reaction. The method takes the easily available o-hydroxyacetophenone (formula 1) as a raw material, uses dimethyl sulfoxide and acetic acid as a mixed solvent to directly obtain the chromanone substance (formula 2) containing the quaternary carbon center at the 3-position through one-pot reaction, and has simple operation and wider substrate application range.
In order to achieve the above object, embodiments of the present invention are as follows:
a preparation method of a chromanone compound containing a quaternary carbon center is characterized by comprising the following steps: taking an o-hydroxyacetophenone compound (formula 1) as a raw material, under the action of sodium acetate and an additive, taking dimethyl sulfoxide and acid as mixed solvents, heating by a one-pot method to obtain a chromanone compound containing a quaternary carbon center and having a structure of formula (2),
wherein R represents hydrogen or a substituent, and n represents an integer of 0, 1, 2, 3 or 4.
In a preferred embodiment of the present invention, the molar ratio of the o-hydroxyacetophenone compound (formula 1) to the dimethyl sulfoxide reactant is 1:3.
In a preferred embodiment of the present invention, wherein R represents hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, nitro, halogen, C 1 -C 6 Alkoxy, cyano, amino, sulfonic acid, halo C 1 -C 6 Alkyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
In a preferred embodiment of the present invention, the acid is a common protonic acid, including formic acid, acetic acid, propionic acid, butyric acid, hydrochloric acid, phosphoric acid, and acetic acid.
In a preferred embodiment of the invention, the additive is selected from the group consisting of amine compounds.
In a preferred embodiment of the invention, the additive is selected from the group consisting of tetrahydropyrrole, morphine, piperidine, proline.
In a preferred embodiment of the present invention, the reaction temperature is 110-140 degrees and the reaction time is 10-30 hours.
In a preferred technical scheme of the invention, the specific reaction steps are as follows:
dissolving an o-hydroxyacetophenone compound shown in a formula 1 in dimethyl sulfoxide, adding sodium acetate, acid and an additive, reacting under heating, removing a solvent and the additive in a reaction liquid after the reaction is completed, extracting a target product by using an organic solvent, merging organic phases, drying, performing reduced pressure rotary evaporation to obtain a crude product, and performing silica gel column chromatography to obtain the chromanone compound containing the quaternary carbon center and having the structure shown in the formula (2).
Further, the reaction can be carried out under the gas conditions of nitrogen, air, oxygen and the like, and after the reaction is finished, the product is separated and purified by adopting a column chromatography method after extraction and drying, so as to obtain the target compound.
In the technical scheme of the invention, dimethyl sulfoxide is used as a diversified reaction unit, and the following reaction intermediates exist in the reaction process, and the intermediates can also react in the same way to obtain the target product of the chromanone compound containing the quaternary carbon center at the 3-position.
In the technical scheme of the invention, DMSO is used as a diversified reaction unit and a reaction solvent, and the dosage is excessive, which belongs to the category of understanding of the person skilled in the art.
In the present application, the term "alkyl" generally refers to a straight or branched hydrocarbon chain radical consisting of only carbon and hydrogen atoms, free of unsaturation, having 1 to 8 carbon atoms and linked by single bonds to the remainder of the molecule, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1, 1-dimethylethyl (tert-butyl). The term "(C) 1-6 ) Alkyl "refers to an alkyl group as defined above having up to 6 carbon atoms.
In the present application, the term "alkenyl" generally refers to straight or branched chain aliphatic hydrocarbon groups containing a carbon-carbon double bond and possibly having from about 2 to about 10 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. The term "(C) 2-6 ) Alkenyl "refers to alkenyl groups having up to 6 carbon atoms as defined above.
In the present application, the term "alkynyl" generally refers to straight or branched hydrocarbon groups having at least one carbon-carbon triple bond and having 2 to 12 carbon atoms (groups having 2 to 10 carbon atoms are currently preferred), such as ethynyl, propynyl and butynyl. The term "(C) 2-6 ) Alkynyl "refers to an alkynyl group having up to 6 carbon atoms as defined above.
In the present application, the term "alkoxy" generally refers to an alkyl, cycloalkyl, cycloalkylalkyl group attached to the rest of the molecule through an oxygen bond as defined above. The term "substituted alkoxy" refers to an alkoxy group wherein the alkyl groups constitute a substituted (i.e., -O- (substituted alkyl)), wherein the term "substituted alkyl" is the same as defined above for "alkyl". For example, "alkoxy" refers to the group-O-alkyl, including combinations of 1-8 carbon atoms in a straight chain, branched, cyclic configuration, and its attachment to the parent structure through oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy.
In this application, the term "halogen" refers to fluorine, chlorine, bromine, iodine, astatine.
In the present application, the term "haloalkyl" refers to an alkyl group substituted with halogen.
The invention has the advantages and positive effects that:
1. the invention provides a new synthesis method for preparing chromanone compound with quaternary carbon center at 3 position by directly activating dimethyl sulfoxide with acetic acid under the condition of simple raw material source and no metal catalysis and providing three different synthesis units to participate in reaction.
2. The invention uses the easily available o-hydroxyacetophenone as the raw material, uses the dimethyl sulfoxide and acetic acid as the mixed solvent to directly obtain the chromanone substance containing quaternary carbon center at the 3-position by a one-pot reaction, and has simple operation and wider substrate application range.
Drawings
FIGS. 1a to 1b are a hydrogen spectrum and a carbon spectrum of a target compound 2a in example 1 of the present invention;
FIGS. 2 a-2 b are the hydrogen and carbon spectra of the target compound 2b in example 2 of the present invention;
FIGS. 3 a-3 b are the hydrogen and carbon spectra of the target compound 2c of example 3 of the present invention;
FIGS. 4a to 4b show the hydrogen spectrum and the carbon spectrum of the target compound 2d in example 4 of the present invention.
Detailed Description
The present invention will be described in detail with reference to the following specific examples, which are not intended to limit the scope of the invention in any way, but are not intended to limit the scope of the invention thereto. All techniques implemented based on the foregoing are within the scope of the invention.
EXAMPLE 1 preparation of Compound 2a, object Compound 2a
The reaction equation is shown below:
1a (0.2 mmol, 24. Mu.L) of sodium acetate (0.16 mmol,13.1 mg), morpholine (0.2 mmol, 18.0. Mu.L) was added to the reaction tube at a time, dissolved in a solvent of dimethyl sulfoxide and acetic acid (2.0 mL/0.35 mL), stirred at 140℃for 30 hours under an air atmosphere, then 10mL of saturated sodium carbonate was added, the organic phase was extracted three times with ethyl acetate, the organic phase was combined, dried over sodium sulfate, and the crude product was purified by column chromatography (silica gel 200-300 mesh) to finally obtain pale yellow liquid compound 2a (32.9 mg, yield 69%). The structure of the compound is confirmed as follows:
1 H NMR(600MHz，CDCl 3 )δ7.87(dd，J＝1.2，7.8Hz，1H)，7.49(td，J＝1.2，7.2Hz，1H)，7.03(t，J＝7.2Hz，1H)，6.97(d，J＝8.4Hz，1H)，4.57(d，J＝12.0Hz，1H)，4.37(d，J＝12.0Hz，1H)，3.91(d，J＝12.0Hz，1H)，3.75(d，J＝12.0Hz，1H)，2.89(d，J＝13.8Hz，1H)，2.84(d，J＝13.8Hz，1H)，2.65(br，1H)，2.17(s，3H)； 13 C NMR(150MHz，CDCl 3 )δ196.3，161.4，136.6，127.7，121.9，119.9，118.0，70.6，62.8，51.0，35.1，18.1；HRMS(EsI)m/z[M+H + ]calcd for C 12 H 15 O 3 S 239.0742，found 239.0745.
the compound synthesized by structural identification is the target compound shown in 2 a.
EXAMPLE 2 preparation of Compound 2b, object Compound
The reaction equation is shown below:
1b (0.2 mmol,30.8 mg), sodium acetate (0.16 mmol,13.1 mg), morpholine (0.2 mmol, 18.0. Mu.L) were added to the reaction tube at a time, dissolved in a solvent of dimethyl sulfoxide and acetic acid (2.0 mL/0.35 mL), stirred at 140℃for 20 hours under an air atmosphere, then 10mL of saturated sodium carbonate was added, the organic phase was extracted three times with ethyl acetate, the organic phase was combined, dried over sodium sulfate, and the filtered, spun-dried crude product was purified by column chromatography (silica gel 200-300 mesh) to finally give compound 2b (32.3 mg, yield 63%) as a pale yellow liquid. The structure of the compound is confirmed as follows:
R f ＝0.25(petrolcum ether/EtOAc 5/1)； 1 H NMR(600MHz，CDCl 3 )δ7.52(dd，J＝3.0，7.8Hz，1H)，7.24-7.20(m，1H)，6.97(dd，J＝3.6，9.0Hz，1H)，4.57(d，J＝11.4Hz，1H)，4.39(d，J＝11.4Hz，1H)，3.93(dd，J＝6.0，11.4Hz，1H)，3.75(d，J＝11.4Hz，1H)，2.87(d，J＝13.8Hz，1H)，2.84(d，J＝13.8Hz，1H)，2.55(br，1H)，2.17(s，3H)； 13 C NMR(150MHz，CDCl 3 )δ195.4，157.6(d，J＝1.5Hz)，157.5(d，J＝241.5Hz)，124.1(d，J＝24.0Hz)，120.4(d，J＝6.0Hz)，119.8(d，J＝7.5Hz)，112.5(d，J＝22.5Hz)，70.9，62.7，51.1，35.0，18.2；HRMS(ESI)m/z[M+H + ]calcd for C 12 H 14 FO 3 S 257.0648，found 257.0645.
the compound synthesized by structural identification is the target compound shown in 2 b.
EXAMPLE 3 preparation of Compound 2c, the target Compound
The reaction equation is shown below:
1c (0.2 mmol,45.8 mg), sodium acetate (0.16 mmol,13.1 mg), morpholine (0.2 mmol, 18.0. Mu.L) were added to the reaction tube at a time, dissolved in a solvent of dimethyl sulfoxide and acetic acid (2.0 mL/0.35 mL), stirred at 140℃for 30 hours under an air atmosphere, then 10mL of saturated sodium carbonate was added, the organic phase was extracted three times with ethyl acetate, the organic phase was combined, dried over sodium sulfate, and the filtered, spun-dried crude product was purified by column chromatography (silica gel 200-300 mesh) to finally give compound 2c (45.0 mg, yield 68%) as a pale yellow liquid. The structure of the compound is confirmed as follows:
R f ＝0.24(petroleum ether/EtOAc 5/1)； 1 H NMR(600MHz，CDCl 3 )δ7.64(s，1H)，7.59(s，1H)，4.68(d，J＝12.0Hz，1H)，4.46(d，J＝12.0Hz，1H)，3.94(d，J＝10.2Hz，1H)，3.75(d，J＝11.4Hz，1H)，2.88(d，J＝13.8Hz，1H)，2.84(d，J＝13.8Hz，1H)，2.44(br，1H)，2.30(s，3H)，2.18(s，3H)； 13 C NMR(150MHz，CDCl 3 )δ195.5，155.8，140.6，132.5，126.9，120.8，111.3，71.3，62.8，51.0，35.1，20.3，18.2；HRMS(ESI)m/z[M+H + ]calcd for C 13 H 16 BrO 3 S 331.0004，found 331.0006.
the compound synthesized through structural identification is the target compound shown in 2 c.
EXAMPLE 4 preparation of Compound 2d of the object Compound
The reaction equation is shown below:
1d (0.2 mmol,38.0 mg), sodium acetate (0.16 mmol,13.1 mg), morpholine (0.2 mmol, 18.0. Mu.L) were added to the reaction tube at a time, dissolved in a solvent of dimethyl sulfoxide and acetic acid (2.0 mL/0.35 mL), stirred at 140℃for 30 hours under an air atmosphere, then 10mL of saturated sodium carbonate was added, the organic phase was extracted three times with ethyl acetate, the organic phase was combined, dried over sodium sulfate, and the filtered, spun-dried crude product was purified by column chromatography (silica gel 200-300 mesh) to finally give compound 2d (43.3 mg, yield 74%) as a pale yellow liquid. The structure of the compound is confirmed as follows:
R f ＝0.27(petroleum ether/EtOAc 5/1)； 1 H NMR(600MHz，CDCl 3 )δ7.57(s，1H)，6.68(s，1H)，4.51(d，J＝11.4Hz，1H)，4.30(d，J＝11.4Hz，1H)，3.89(d，J＝11.4Hz，1H)，3.74(d，J＝11.4Hz，1H)，2.89(d，J＝13.8Hz，1H)，2.84(d，J＝13.8Hz，1H)，2.77-2.72(m，4H)，2.69(br，1H)，2.18(s，3H)，1.77(m，4H)； 13 C NMR(150MHz，CDCl 3 )δ196.5，159.1，147.9，131.4，127.5，117.9，117.3，70.5，62.9，50.9，35.2，30.3，28.6，23.2，22.7，18.1；HRMS(ESI)m/z[M+H + ]calcd for C 16 H 21 O 3 S 293.1211，found 293.1214.
the compound synthesized through structural identification is the target compound shown in 2 d.
Although embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that: various substitutions, changes and modifications are possible without departing from the spirit and scope of the invention and the appended claims, and therefore the scope of the invention is not limited to the disclosure of the embodiments.
Claims (8)
1. A preparation method of a chromanone compound containing a quaternary carbon center is characterized in that an o-hydroxyacetophenone compound (formula 1) is used as a raw material, dimethyl sulfoxide and acid are used as mixed solvents to obtain the chromanone compound containing the quaternary carbon center with a structure of formula 2 by a one-pot heating method under the action of sodium acetate and additives,
wherein R represents hydrogen or a substituent, and n represents an integer of 0, 1, 2, 3 or 4.
2. The method according to claim 1, wherein the molar ratio of the o-hydroxyacetophenone compound (formula 1) to dimethyl sulfoxide is 1:3.
3. A process according to claim 1 or 2, wherein R represents hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, nitro, halogen, C 1 -C 6 Alkoxy groupCyano, amino, sulfonic acid, halogenated C 1 -C 6 Alkyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl.
4. The method of claim 1, wherein the acid is a common protic acid, including formic acid, acetic acid, propionic acid, butyric acid, hydrochloric acid, phosphoric acid, acetic acid.
5. The method of claim 1, wherein the additive is selected from the group consisting of amine compounds.
6. The method of claim 1, wherein the additive is selected from the group consisting of tetrahydropyrrole, morphine, piperidine, proline.
7. The method according to claim 1, wherein the reaction temperature is 110 to 140 degrees and the reaction time is 10 to 30 hours.
8. The method according to claim 1, wherein the reaction comprises the following specific steps:
dissolving an o-hydroxyacetophenone compound shown in a formula 1 in dimethyl sulfoxide, adding sodium acetate, acid and an additive, reacting under heating, removing a solvent and the additive in a reaction liquid after the reaction is completed, extracting a target product by using an organic solvent, merging organic phases, drying, performing reduced pressure rotary evaporation to obtain a crude product, and performing silica gel column chromatography to obtain the chromanone compound containing a quaternary carbon center and having the structure shown in the formula 2.
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Citations (4)
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| DE10054932A1 (en) * | 2000-11-06 | 2002-05-08 | Bayer Ag | Antiviral medicaments containing new or known chroman-4-one or chroman-4-one derivatives, especially effective against hepatitis B virus infections |
| CN1861590A (en) * | 2006-06-14 | 2006-11-15 | 浙江大学 | Flavoneoid derivative and its preparation process and use |
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| CN107759550A (en) * | 2016-08-22 | 2018-03-06 | 沅江华龙催化科技有限公司 | The method of o-hydroxyacetophenone class compound α H while functionalization and the hexa-atomic miscellaneous oxygen cycle compound of Cyclization benzo |
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| DE10054932A1 (en) * | 2000-11-06 | 2002-05-08 | Bayer Ag | Antiviral medicaments containing new or known chroman-4-one or chroman-4-one derivatives, especially effective against hepatitis B virus infections |
| CN1861590A (en) * | 2006-06-14 | 2006-11-15 | 浙江大学 | Flavoneoid derivative and its preparation process and use |
| CN101486713A (en) * | 2009-02-09 | 2009-07-22 | 沈阳药科大学 | Furo[2,3-h] chromene compound and use for preventing platelet aggregation |
| CN107759550A (en) * | 2016-08-22 | 2018-03-06 | 沅江华龙催化科技有限公司 | The method of o-hydroxyacetophenone class compound α H while functionalization and the hexa-atomic miscellaneous oxygen cycle compound of Cyclization benzo |
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