CN109824601B - Method for synthesizing chiral cyclic urea through asymmetric hydrogenation of iridium-catalyzed 2-hydroxypyrimidine compound - Google Patents
Method for synthesizing chiral cyclic urea through asymmetric hydrogenation of iridium-catalyzed 2-hydroxypyrimidine compound Download PDFInfo
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Abstract
The invention provides a chiral ring synthesized by asymmetric hydrogenation of an iridium-catalyzed 2-hydroxypyrimidine compoundA process for the preparation of urea-like compounds,
in the formula: r is C1-C6 alkyl or aryl; r' is aryl, heteroaryl or alkyl containing substituent groups, wherein the substituent groups are F, Cl and CF3Me and MeO. The synthesized chiral cyclic urea has an enantiomeric excess of 96%. The method has the advantages of simple, convenient, practical and feasible operation, high yield, environment friendliness, commercial availability of the catalyst, mild reaction conditions and potential practical application value.
Description
Technical Field
The invention relates to a method for synthesizing chiral cyclic urea by catalyzing asymmetric hydrogenation of a 2-hydroxypyrimidine compound with high enantioselectivity by using an iridium catalytic system.
Background
The asymmetric hydrogenation of heteroaromatic compounds has been a great progress in recent years. Various heteroaromatic compounds such as: isoquinoline, pyridine, quinoline, pyrazine and the like can all obtain corresponding heterocyclic compounds through asymmetric catalysis, wherein the corresponding heterocyclic compounds can be obtained through asymmetric catalysis (refer to the first publication, (a) Lu, S.M.; Wang, Y.Q.; Han, X.W.; Zhou, Y.G.Angew.chem.Int.Ed.2006, 45,2260.(b) Ye, Z-S.; Chen, M.W.; Chen, Q.A.; Shi L.; Duan, Y.; Zhou, Y.G.Angew.chem.Int.Ed.2012, 51,10181.(c) Wang, W.B.; Lu S.M.; Yang, P.Y.; Han, X.W.; Zhou Y.J.am.Soc.; Lu S-M.; Yang.P.Y.; Han, X.W.; Zhou Y.J.C.; Chen J.S.125, W.; W.M.I.E.E.E.E.E.E.D.; F.; W.E.E.I.; F.E.E.I.I.52, W.; F.; F.I.I. F.; F.I.I.I.I.. The challenges are: firstly, aromatic compounds have strong stability and generally require relatively harsh conditions to react, and the enantioselectivity of the reaction is difficult to control under the conditions; secondly, the aromatic heterocyclic compound usually contains heteroatoms which are easy to coordinate with the catalyst, such as nitrogen, oxygen, sulfur and the like, and is easy to cause catalyst poisoning and inactivation; and thirdly, secondary coordination groups are usually lacking in the aromatic compounds, which is not favorable for the action of substrates and catalysts. If a functional group (such as hydroxyl, sulfydryl, amino and the like) with potential isomerization is introduced into the ortho position of the aromatic heterocyclic nitrogen, the aromaticity, the chemical activity, the biological property and the like of the aromatic compound are obviously influenced. It is worth mentioning that when a hydroxyl group is introduced at the 2-position of pyrimidine, there is an isomerization equilibrium of an alcoholic and a ketone type, and in a protic solvent, the isomerization equilibrium system is dominated by the ketone type, and the ketone type structure has a reduced aromaticity compared to the alcoholic structure, thereby increasing the activity of the substrate to some extent, and we speculate that this type of substrate is more easily hydrogenated in a hydrogenation system.
In 2015, the Glorius group developed a ruthenium/N-heterocyclic carbene complex to catalyze the hydrogenation of pyridone substrates, which gave cyclic lactams in excellent yields, but with poor enantioselectivity (ref: Wysocki, J.; Schlephorst, C.; Glorius. F. Synlett.2015,26,1557.);
subsequently, the week group successfully achieved asymmetric hydrogenation of 3-hydroxypyrazole using a palladium catalytic system with good results, but the substrate range was limited to fluorine-containing compounds (reference III: Chen, Z. -P.; Chen, M. -W.; Shi, L.; Yu, C. -B.; Zhou, Y. -G.Chem.Sci.2015,6,3415.).
Disclosure of Invention
The invention aims to provide a method for synthesizing a chiral cyclic urea compound by asymmetrically hydrogenating a 2-hydroxypyrimidine compound under the catalysis of iridium, and in order to realize the aim, the technical scheme adopted by the invention is as follows: a method for synthesizing chiral cyclic urea by asymmetric hydrogenation of 2-hydroxypyrimidine compounds under the catalysis of iridium,
in the formula: r is C1-C6 alkyl or aryl; r' is aryl, heteroaryl or alkyl containing substituent groups, wherein the substituent groups are F, Cl and CF3At least one of Me and MeO;
preferably, the asymmetric hydrogenation reaction comprises two stages, catalyst preparation and substrate hydrogenation
(1) Catalyst preparation
Mixing an iridium metal precursor, a chiral ligand and an organic solvent, and stirring at normal temperature for 10-20 minutes to obtain the catalyst
(2) Hydrogenation reaction
Adding the obtained catalyst, additive and organic solvent into a 2-hydroxypyrimidine substrate, transferring the substrate into a high-pressure kettle, charging hydrogen gas for 100-1000 psi, and stirring at 25-80 ℃ for 12-24 hours to generate a product.
The organic solvent is preferably at least one selected from the group consisting of toluene, tetrahydrofuran, dichloromethane, ethyl acetate, 1, 4-dioxane, methanol, ethanol and isopropanol.
The iridium metal precursor is preferably selected from methoxy (cyclooctadiene) iridium dimer, bis (cyclooctene) iridium chloride dimer, 1, 5-cyclooctadieneiridium chloride dimer or bis (1, 5-cyclooctadiene) iridium tetrakis [3, 5-bis (trifluoromethyl) phenyl ] boronic acid.
The chiral ligand is preferably selected from (1R,1 'R, 2S, 2' S) -DuanPhos, (S, S) -MeDuPhos, (R) -DifluorPhos, (R) -MeOBiphep, (R) -SegPhos, (R) - (S) -Cy2PF-PtBu2Preferably the bisphosphine ligand: (R) -SegPhos, and (S, S) -f-Binaphane.
Preferably, the feeding proportion of the method is as follows: the molar ratio of the metal precursor, the chiral ligand, the additive and the substrate of the iridium is as follows: 0.01-0.05:0.022-0.110:0.04-0.10:1.
Preferably, the additive is trichloroisocyanuric acid, iodine, N-bromosuccinimide.
The asymmetric hydrogenation reaction is carried out at a reaction pressure of 100-1200psi, preferably 400-800 psi, and a reaction temperature of 0-100 deg.C, preferably 25-80 deg.C.
When an isomerization functional group is introduced into an aromatic compound, the aromaticity can be reduced to a certain extent, so that the activity of a substrate is improved, and the substrate is easier to be hydrogenated.
The invention has the beneficial effects
1. The reaction system is clean, the enantioselectivity of the product is good, and the highest ee can be obtained by 95 percent;
2. chiral cyclic urea compounds can be well obtained;
3. the catalyst is convenient to prepare, and the reaction operation is simple, convenient and practical;
4. the hydrogenation reaction condition is mild.
Detailed Description
The present invention will be described in detail by way of examples, which are given as alternatives, but are not limited thereto.
The asymmetric hydrogenation reaction comprises two stages of catalyst preparation and substrate hydrogenation
(1) Preparing a catalyst, namely adding an iridium metal precursor and a chiral diphosphine ligand into an organic solvent, stirring for 10 minutes at room temperature, and directly using the mixture in the hydrogenation reaction of 2-hydroxypyrimidine.
(2) And (3) hydrogenation reaction, namely adding the catalyst and the organic solvent into a substrate, sealing the substrate into a hydrogenation kettle, introducing hydrogen, and stirring the mixture for 12 to 24 hours at a temperature of between 25 and 80 ℃ to generate a product. The reaction conditions were as follows: under the protection of nitrogen, adding the catalyst and the organic solvent into an ampoule of a 2-hydroxypyrimidine substrate, moving the ampoule into a reaction kettle, introducing hydrogen, reacting for 12-24 hours at a certain temperature, releasing the hydrogen, decompressing, concentrating, removing the solvent, and performing column chromatography separation to obtain the target product.
The catalyst is a complex of iridium metal precursor and diphosphine ligand, and the iridium metal precursor and the diphosphine ligand are commercially available without any treatment.
Examples 1-13 optimization of reaction conditions for hydrogenation of disubstituted substrates
Adding 1, 5-cyclooctadiene iridium chloride dimer (0.5-5 mol% of the dosage of a substrate) and chiral diphosphine ligand (1.1-11 mol% of the dosage of the substrate) into a reaction bottle, replacing with nitrogen, adding an organic solvent (1.0-4.0mL), and stirring at room temperature for 10 minutes; then transferring the solution into a reaction bottle which is pre-filled with a substrate 1a (0.1mmol) and an additive (5 mol% -30 mol% of the substrate amount) by using an organic solvent (1.0-2.0mL), moving the reaction bottle into a reaction kettle, introducing hydrogen (400psi-800psi), and reacting for 24 hours at 40-80 ℃; releasing hydrogen, removing the solvent, and directly performing column chromatography separation to obtain a target product, wherein the reaction formula and the ligand structure are as follows:
note: in the formula [ Ir (COD) Cl]2Is 1, 5-cyclooctadiene iridium chloride dimer, chiral ligand, Additive and Solvent.
The yield was the conversion, the enantiomeric excess of the product was determined by chiral liquid chromatography and is detailed in table 1.
TABLE 1 asymmetric hydrogenation optimization of 2-hydroxypyrimidine 1aa
Examples 14-19 Iridium catalyzed asymmetric hydrogenation of disubstituted substrates to synthesize chiral cyclic ureas 2
1, 5-cyclooctadiene iridium chloride dimer (1.0 mol% of the amount of the substrate) and (S, S) -f-Binaphane (2.2 mol% of the amount of the substrate) were put into a reaction flask, and after nitrogen substitution, an organic solvent (1.0mL) was added and the mixture was stirred at room temperature for 10 minutes; then transferring the solution into an ampoule with a substrate 1(0.3mmol) and trichloroisocyanuric acid (10 mol%) in advance by using an organic solvent (2.0mL), transferring the ampoule into a reaction kettle, introducing hydrogen (800psi), and reacting at 40 ℃ for 24 hours; releasing hydrogen, removing the solvent, and directly performing column chromatography separation to obtain a pure product, wherein the reaction formula is as follows:
note: in the formula [ Ir (COD) Cl]2Is 1, 5-cyclooctadiene iridium chloride dimer, (S, S) -f-bindhane is chiral ligand, TCCA is trichloroisocyanuric acid, DCM is dichloromethane.
The yields were isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography, see table 2.
TABLE 2 Iridium catalyzed asymmetric hydrogenation synthesis of chiral cyclic ureas 2a
Example 3: method for synthesizing chiral cyclic urea by hydrogenating monosubstituted substrate
1, 5-cyclooctadiene iridium chloride dimer (1.0 mol% of the amount of the substrate) and (R) -C were charged into a reaction flask1TunePhos (2.2 mol% of substrate), after nitrogen substitution, organic solvent (1.0mL) was added and stirred at room temperature for 0.5 hour; then transferring the solution into an ampoule with substrate 3(0.3mmol) and 1, 3-dichloro-5, 5-dimethylhydantoin (10 mol%) in advance by using an organic solvent (2.0mL), transferring the solution into a reaction kettle, introducing hydrogen (800psi), and reacting for 24 hours at 40 ℃; releasing hydrogen, removing the solvent, and directly performing column chromatography separation to obtain a pure product, wherein the reaction formula is as follows:
note: in the formula [ Ir (COD) Cl]2Is 1, 5-cyclooctadiene iridium chloride dimer, (R) -C1-TunePhos is a chiral ligand,
DCDMH is 1, 3-dichloro-5, 5-dimethylhydantoin and THF is tetrahydrofuran.
The yields were isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography, see table 3.
TABLE 3 Iridium catalyzed asymmetric hydrogenation of chiral cyclic ureas 3a
(4R,6R)-4-methyl-6-phenyltetrahydropyrimidin-2(1H)-one(2a):92％yield,95％ee.1H NMR(400
Claims (6)
1. A method for synthesizing chiral cyclic urea by asymmetric hydrogenation of 2-hydroxypyrimidine compounds under the catalysis of iridium is characterized in that,
in the formula:
r is C1-C6 alkyl or aryl;
r' is aryl, heteroaryl or alkyl containing substituent groups,
the substituent is F, Cl or CF3At least one of Me and MeO;
the additive is trichloroisocyanuric acid, iodine and N-bromosuccinimide.
2. The process of claim 1, wherein the asymmetric hydrogenation reaction comprises two stages of catalyst preparation and substrate hydrogenation:
(1) catalyst preparation
Mixing an iridium metal precursor, a chiral ligand and an organic solvent, and stirring at normal temperature for 10-20 minutes to obtain a catalyst;
(2) substrate hydrogenation
Adding the obtained catalyst, additive and organic solvent into a 2-hydroxypyrimidine substrate, transferring the substrate into a high-pressure kettle, charging hydrogen gas for 100-1000 psi, and stirring at 25-80 ℃ for 12-24 hours to generate a product.
3. The method of claim 2, wherein the organic solvent is selected from at least one of toluene, tetrahydrofuran, methylene chloride, ethyl acetate, 1, 4-dioxane, methanol, ethanol, and isopropanol.
4. The process of claim 1 or 2, wherein the iridium metal precursor is selected from methoxy (cyclooctadiene) iridium dimer, bis (cyclooctene) iridium chloride dimer, 1, 5-cyclooctadiene iridium chloride dimer, or bis (1, 5-cyclooctadiene) iridium tetrakis [3, 5-bis (trifluoromethyl) phenyl ] boronic acid.
5. The method of claim 1 or 2Characterized in that the chiral ligand is selected from (1)R,1’R,2S,2’S)-DuanPhos, (S,S)-MeDuPhos, (R)-DifluorPhos, (R)-MeOBiphep, (R)-SegPhos, (R)-(S)-Cy2PF-P t Bu2。
6. The method according to claim 1, characterized in that the method is carried out in the following feed ratios: the iridium metal precursor, the chiral ligand, the additive and the 2-hydroxypyrimidine compound are in the following molar ratio: 0.01-0.05:0.022-0.110:0.04-0.10: 1.
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| CN103387533A (en) * | 2012-05-08 | 2013-11-13 | 中国科学院大连化学物理研究所 | Method for synthesis of chiral piperidine derivative through iridium-catalyzed asymmetric hydrogenation of pyridine |
| CN104710406A (en) * | 2013-12-13 | 2015-06-17 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by iridium |
| WO2015142001A2 (en) * | 2014-03-21 | 2015-09-24 | 충남대학교산학협력단 | Compound having cardiotonic activity and pharmaceutical composition for preventing or treating heart failure, containing same |
| CN105693598A (en) * | 2014-11-28 | 2016-06-22 | 中国科学院大连化学物理研究所 | Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation |
| CN106995413A (en) * | 2016-01-25 | 2017-08-01 | 中国科学院大连化学物理研究所 | A kind of method of iridium catalytic hydrogenation asymmetric syntheses bridged piperazine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103387533A (en) * | 2012-05-08 | 2013-11-13 | 中国科学院大连化学物理研究所 | Method for synthesis of chiral piperidine derivative through iridium-catalyzed asymmetric hydrogenation of pyridine |
| CN104710406A (en) * | 2013-12-13 | 2015-06-17 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by iridium |
| WO2015142001A2 (en) * | 2014-03-21 | 2015-09-24 | 충남대학교산학협력단 | Compound having cardiotonic activity and pharmaceutical composition for preventing or treating heart failure, containing same |
| CN105693598A (en) * | 2014-11-28 | 2016-06-22 | 中国科学院大连化学物理研究所 | Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation |
| CN106995413A (en) * | 2016-01-25 | 2017-08-01 | 中国科学院大连化学物理研究所 | A kind of method of iridium catalytic hydrogenation asymmetric syntheses bridged piperazine derivatives |
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