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DEVELOPMENT OF NOVEL RADICAL ION REACTIVITY USING ORGANIC PHOTOREDOX CATALYSIS
Chapel Hill ; The University of North Carolina at Chapel Hill,2022.
Abstract: Photoredox catalysis has traditionally been accomplished by using ruthenium or iridium polypyridyl complexes. These complexes, while robust in their application, can prove to be quite cost prohibitive. Additionally, their respective redox windows are relatively narrow, limiting the scope of substrates with which they can undergo photoinduced electron transfer. Visible light absorbing organic chromophores have proven to be cost effective alternatives to precious transition metal photoredox catalysts. Additionally, the excited state redox potentials of organic photoredox catalysts can be significantly greater than that of their inorganic counterparts allowing for the development of new methodologies on substrates that could not otherwise undergo photoinduced electron transfer. In particular, organic acridinium dyes possess photophysical properties that make them extremely potent excited state oxidants. More recently it has been demonstrated that the acridine radical in the excited state possesses and excited state oxidation potential comparable to that of dissolving metal reductants making it an excellent excited state reductant. Herein, we describe methods developed that leverage the 5.51 V of redox potential that acridinium complexes can access. Nucleophilic aromatic substitution (SNAr) is a common method for arene functionalization; however, reactions of this type are typically limited to electron-deficient aromatic halides. Herein, we describe a mild, metal_x005f_x0002_free, cation-radical accelerated nucleophilic aromatic substitution (CRA-SNAr) using a potent acridinium photoredox catalyst as an excited state oxidant. Selective substitution of arene C−O bonds on a wide array of aryl ether substrates was shown with a variety of primary amine nucleophiles. Mechanistic evidence is also presented that supports the proposed CRA-SNAr pathway. Ketone–olefin coupling reactions are common methods for the formation of carbon–carbon bonds. This reaction class typically requires stoichiometric or super stoichiometric quantities of metal reductants and catalytic variations are limited in application. Photoredox catalysis has offered an alternative method towards ketone–olefin coupling reactions, although most methods are limited in scope to easily reducible aromatic carbonyl compounds. Herein, we describe a mild, metal-free ketone–olefin coupling reaction using an excited state acridine radical super reductant as a photoredox catalyst. We demonstrate both intra and intermolecular ketone–olefin couplings of aliphatic and aromatic ketones and aldehydes. Mechanistic evidence is also presented supporting an “olefin first”ketone–olefin coupling mechanism.
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CAS No. : | 1131-62-0 |
Formula : | C10H12O3 |
M.W : | 180.20 |
SMILES Code : | CC(C1=CC=C(OC)C(OC)=C1)=O |
MDL No. : | MFCD00008737 |
InChI Key : | IQZLUWLMQNGTIW-UHFFFAOYSA-N |
Pubchem ID : | 14328 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.62 |
TPSA ? Topological Polar Surface Area: Calculated from | 35.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 2.19 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.44 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 1.13 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.19 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.77 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.01 |
Solubility | 1.77 mg/ml ; 0.00982 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -1.79 |
Solubility | 2.91 mg/ml ; 0.0162 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -2.99 |
Solubility | 0.186 mg/ml ; 0.00103 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -6.38 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 1.5 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydroxide; In ethanol; water; at 27℃; for 4.0h; | Example 5(E)-l-(3,4-dimethoxyphenyl)-3-(6-(trifluoromethyl) imidazo [2,1- b] thiazol-5-yl)Prop-2-en-l-one (8f)To a stirred solution 3,4-dimethoxyphenyl acetophenone (180 mg, 2.7 mmol) and a 6- (trifluoromethyl) imidazo [2,1-b] thiazole-5-carbaldehyde (246 mg, 2.7 mmol) in ethanol (20ml) 10% aqueous solution of NaOH was added (5ml). The reaction mixture was stirred at room temperature 27C for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate / water. The organic layer was washed with brine and evaporated. This was further purified by columnchromatography using ethyl acetate: hexane (2:8) as a solvent system to obtain the pure product (8f) as yellow solid (306 mg, 75% yield). Mp: 167-169 C'H NMR (CDC13, 300 MHz), delta 3.97 (s, 6H), 6.93 (d, 1H, J= 9.065 Hz), 7.19 (d, 1H, J = 4.53. Hz), 7.41 (d, 1H, J= 15.86 Hz ), 7.57 -7.61 (m, 2H), 7.83 (d, 1H, J= 4.53 Hz), 7.91 (d, 1H J= 15.86 Hz) , ESI-MS:382.35 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; at 20℃; for 24h; | General procedure: The relevant N-methyl intermediate (3a-c, 2 mmol), acetophenonederivate (2 mmol) and potassium hydroxide (6 mmol) wasdissolved in ethanol (20 mL) and stirred for 24 h. Then the reactionmixture was filtered and washed with water and cold ethanol. Thecrude product was purified by recrystallization from ethanol anddichloromethane to give pure chalcone (4a-q) with yields of34.2-93.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With iodine; In dimethyl sulfoxide; at 20 - 110℃; for 2h; | 2.3 g of 3,4-dimethoxyacetophenone was dissolved in 10 mL of DMSO.Slowly add 1.8g iodine,Drop at room temperatureAdd 2.3g<strong>[16313-65-8]<strong>[16313-65-8]2-Amino-5-nitrobenzamid</strong>e</strong> dissolved in 20mLa solution of DMSO,The reaction was carried out at 110 C for 2 h.150 mL of water was added to the reaction system.Extracted with (3 x 50 mL) ethyl acetate.Reuse (2 × 40mL)Washing with saturated NaHSO3 solution to remove iodine,After washing with water, dried over anhydrous magnesium sulfate.Evaporate the solvent under reduced pressure.The residue was separated by chromatography (eluent: ethyl acetate: petroleum ether = 1:2).2-(3,4-dimethoxybenzoyl)-6-nitro-4(3H)-quinazolinone 3.1 g,Yield 67%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; | General procedure: To a solution of 3,3-bis(methylsulfanyl)methylenemalononitrile 1 (1.70 g, 10 mmol) in 20 mL of DMSO, keton 2a - j (10 mmol) and powdered sodium hydroxide (0.8 20 mmol) were added, and the mixture was magnetically stirred for 4 - 5 h at room temperature. After addition of 300 mL of water to the mixture, the solution was stirred for 12 h at room temperature. The formed precipitate was collected by filtra- tion and washed several times with water. After drying under air, the formed product was recrystallized using methanol or ethanol to obtain the pure products. |
Tags: 1131-62-0 synthesis path| 1131-62-0 SDS| 1131-62-0 COA| 1131-62-0 purity| 1131-62-0 application| 1131-62-0 NMR| 1131-62-0 COA| 1131-62-0 structure
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