Structure of 5980-97-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Zhou, Tongliang ; Gao, Pengcheng ; Bisz, Elwira ; Dziuk, Błażej ; Lalancette, Roger ; Szostak, Roman , et al.
Abstract: We describe the development of [(NHC)Pd(cinnamyl)Cl] complexes of ImPy (ImPy = imidazo[1,5-a]pyridin-3-ylidene) as a versatile class of precatalysts for cross-coupling reactions. These precatalysts feature fast activation to monoligated Pd(0) with 1:1 Pd to ligand ratio in a rigid imidazo[1,5-a]pyridin-3-ylidene template. Steric matching of the C5-substituent and N2-wingtip in the catalytic pocket of the catalyst framework led to the discovery of ImPyMesDipp as a highly reactive imidazo[1,5-a]pyridin-3-ylidene ligand for Pd-catalyzed cross-coupling of nitroarenes by challenging C–NO2 activation. Kinetic studies demonstrate fast activation and high reactivity of this class of well-defined ImPy–Pd catalysts. Structural studies provide full characteristics of this new class of imidazo[1,5-a]pyridin-3-ylidene ligands. Computational studies establish electronic properties of sterically-restricted imidazo[1,5-a]pyridin-3-ylidene ligands. Finally, a scalable synthesis of C5-substituted imidazo[1,5-a]pyridin-3-ylidene ligands through Ni-catalyzed Kumada cross-coupling is disclosed. The method obviates chromatographic purification at any of the steps, resulting in a facile and modular access to ImPy ligands. We anticipate that well-defined [Pd–ImPy] complexes will find broad utility in organic synthesis and catalysis for activation of unreactive bonds.
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CAS No. : | 5980-97-2 |
Formula : | C9H13BO2 |
M.W : | 164.01 |
SMILES Code : | OB(C1=C(C)C=C(C)C=C1C)O |
MDL No. : | MFCD00236060 |
InChI Key : | BZXQRXJJJUZZAJ-UHFFFAOYSA-N |
Pubchem ID : | 292184 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 51.17 |
TPSA ? Topological Polar Surface Area: Calculated from |
40.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.92 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.29 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.26 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.63 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.82 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.37 |
Solubility | 0.699 mg/ml ; 0.00426 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.39 |
Solubility | 0.663 mg/ml ; 0.00404 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.44 |
Solubility | 0.594 mg/ml ; 0.00362 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 |
No |
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) |
No |
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 |
-5.94 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 |
1.0 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) |
1.53 |
* 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 |
---|---|---|
0.05 g of tetrakistriphenylphosphine palladium was added at room temperature to a solution having 0.21 g of 3-bromo-acetoanilide obtained by (1) dissolved in 5 ml of toluene, followed by stirring for 15 minutes. 0.25 g of 2,4, 6-trimethylphenyl boronic acid,. 2 ml of ethanol and 3 ml of a 2M sodium carbonate solution were sequentially added thereto, and the reaction system was flushed with nitrogen, followed by stirring for 12 hours under reflux under heating. After cooling, 10 ml of cold water was added, followed by extraction with 15 ml and 10 ml of ethyl acetate. The organic layers were put together and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel (Silica gel 60N; spherical and neutral, manufactured by Kanto Kagaku) column chromatography (developing solvent of n-hexane: ethyl acetate=2: 1) to obtain 0.15 g of the objective compound having a melting point of 173. 8C. Further, NMR of this compound was as follows. H-NMR 5 (ppm) 1. 98 (s, 6H), 2.15 (s, 3H), 2. 30 (s, 3H), 6. 85 (d, lH ; J =8. 0 Hz), 6. 90 (s, 2H), 7.16 (s, lH), 7. 33 (t, lH; J =8. 0 Hz), 7.41 (bs, lH), 7.57 (d, lH; J =8.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 100℃; for 24h;Inert atmosphere; Schlenk technique; | Under an argon atmosphere, in a Schlenk flask,Followed by loading 3mmol of <strong>[10485-09-3]2-bromoindene</strong> (Shanghai Bi Pharmaceutical Technology Co., Ltd.)1.5 mmol of 2,4,6-trimethylphenylboronic acid (Shanghai Bi Pharmaceutical Technology Co., Ltd.),3 mmol% of tetrakistriphenylphosphine palladium, 6 mmol% of S-Phos and 3 mmol of potassium phosphate,A mixture of 20 mL of toluene and 10 mL of water was added to dissolve the reaction. The reaction was carried out at 100 C for 24 hours,After cooling, the reaction mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the organic phase solvent was removed,Column chromatography on petroleum ether (Rf = 0.8) gave 2- (2,4,6-trimethylphenyl) indene,The yield is 90% |
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