Structure of 21524-34-5
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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. : | 21524-34-5 |
Formula : | C15H23Br |
M.W : | 283.25 |
SMILES Code : | CC(C1=CC(C(C)C)=C(Br)C(C(C)C)=C1)C |
MDL No. : | MFCD00051547 |
InChI Key : | FUMMYHVKFAHQST-UHFFFAOYSA-N |
Pubchem ID : | 140846 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.6 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 77.88 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.81 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
5.99 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
5.82 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
5.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
5.63 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
5.36 |
Log S (ESOL):? ESOL: Topological method implemented from |
-5.45 |
Solubility | 0.00101 mg/ml ; 0.00000355 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-5.77 |
Solubility | 0.000484 mg/ml ; 0.00000171 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.71 |
Solubility | 0.000547 mg/ml ; 0.00000193 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
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) |
Yes |
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 |
-3.77 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
1.0 |
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 |
2.0 |
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) |
1.98 |
* 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 |
---|---|---|
28% | EXAMPLE TEN: Synthesis of Ligand 7; An oven-dried three-neck 250 mL round bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (559 mg, 24.3 mmol), was fitted with a reflux condenser, addition funnel, and glass stopper. The flask was purged with argon and then THF (15 mL) and 2,4,6-triisopropylbromobenzene (2.83 g, 10 mmol) were added via syringe. The reaction mixture was heated to reflux and 1 ,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1 h and then the addition funnel, which was charged with l,2-dibromo-3,4,5,6-tetramethylbenzene (2.92 g, 10 mmol) in 40 mL of THF, was opened and the solution was added over a 1 h period. The mixture was stirred for 5 h at reflux and then cooled to room temperature where CuCl (1.0 g, 10 mmol) was added quickly to the reaction mixture. Next, ClPCy2 (2.65 mL, 10 mmol) was then added in a dropwise fashion and the reaction mixture was heated to 75 0C for 60 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, washed 3 times with 30% NH4OH, dried over MgSO4, and concentrated under reduced pressure. The crude material was recrystallized from benzene to yield the product as a white solid (1.507 g, 28% yield). 1H NMR (300 MHz, CDCl3) δ: 7.36 (s, 5H), 7.15 (s, 2H), 2.99 (septet, J= 7.0 Hz, IH), 2.44 (s, 3H), 2.35-2.14 (m, HH), 1.98 (s, 2H), 1.80-1.44 (m, 14H), 1.39-1.04 (m, 22H), 0.91 (d, J= 6.5 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 150.9, 145.8, 145.4, 144.6, 140.0, 138.5, 135.8, 135.6, 135.5, 135.5, 128.6, 124.3, 40.2, 39.9, 35.4, <n="123"/>35.2, 34.5, 30.7, 29.5, 27.8, 27.7, 27.4, 27.2, 25.9, 25.0, 24.6, 21.2, 20.8, 17.7, 17.3 ppm (Observed complexity is due to P-C splitting). 31P NMR (121 MHz, CDCl3) δ: 16.33 ppm. |
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