Structure of 4-Bromo-2-methoxypyridine
CAS No.: 100367-39-3
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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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Arylboration of Enecarbamates for the Synthesis of Borylated Saturated N-Heterocycles
Grace L. Trammel ; Prashansa B. Kannangara ; Dmytro Vasko ; Oleksandr Datsenko ; Pavel Mykhailiuk ; M. Kevin Brown
Abstract: Two catalytic systems have been developed for the arylboration of endocyclic enecarbamates to deliver synthetically versatile borylated saturated Nheterocycles in good regio- and diastereoselectivities. A Cu/Pd dual catalytic reaction enables the synthesis of borylated, α-arylated azetidines, while a Ni-catalysed arylboration reaction efficiently functionalizes 5-, 6-, and 7-membered enecarbamates. In the case of the Cu/Pdsystem, a remarkable additive effect was identified that allowed for broader scope. The products are synthetically useful, as demonstrated by manipulations of the boronic ester to access biologically active compounds.
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Keywords: Alkene ; Arylation ; Boron ; Cross Coupling ; Heterocycle
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CAS No. : | 100367-39-3 |
Formula : | C6H6BrNO |
M.W : | 188.02 |
SMILES Code : | COC1=NC=CC(Br)=C1 |
MDL No. : | MFCD08277268 |
InChI Key : | YFTGMMXMLPTTAY-UHFFFAOYSA-N |
Pubchem ID : | 14062309 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 38.43 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.82 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.06 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.85 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.33 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.04 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.82 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.73 |
Solubility | 0.349 mg/ml ; 0.00186 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.15 |
Solubility | 1.32 mg/ml ; 0.00702 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.01 |
Solubility | 0.185 mg/ml ; 0.000986 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 |
-5.98 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) |
1.73 |
* 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 |
---|---|---|
95% | With potassium carbonate; In dimethyl sulfoxide; | a) 4-(2-Chloro-4-methoxyphenyl)-2-methoxypyridine A mixture of 4-bromo-2-methoxypyridine (1.20 g, 6.38 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (2.38 g, 12.8 mmol), and potassium carbonate (2.65 g, 19.1 mmol) in anhydrous DMSO (12 mL) was degassed for several minutes with argon. Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (261 mg, 0.32 mmol) was added and, after degassing briefly with argon again, the flask was sealed, and the reaction was heated to 90 C. and stirred for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate, washed with 5% lithium chloride solution (4*), dried over sodium sulfate, filtered, and concentrated. Flash chromatography (80 g ISCO Gold column, 2%-20% ethyl acetate/hexanes) provided the title compound (1.51 g, 95%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 8.19 (d, J=5.0 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.96 (d, J=5.0 Hz, 1H), 6.88 (dd, J=8.3, 2.3 Hz, 1H), 6.08 (s, 1H), 3.98 (s, 3H), 3.84 (s, 3H); ESI MS m/z 250 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; | To a solution of II (2.00 g, 10.6 mmol) in DMF (21 mL) was added NCS (2.98 g, 22.3 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water, diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgS04, and concentrated. The crude product was purified by silica chromatography to provide 1J (2.15 g, 9.18 mmol, 86percent yield) as a white solid. LC-MS Anal. Calc'd for C6H5BrClNO: 220.92, found [M+H] 223.8. 1H NMR (400 MHz, CDC13) delta 8.15 (s, 1H), 7.05 (s, 1H), 3.91 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In dimethyl sulfoxide; at 95℃; | To a solution of compound 1 (2.0g, leq) in DMSO were added compound 2 (1 g, leq), PdC idppf) (0.77 g, O.leq) and K2C03(2.9g, 2eq). The mixture was stirred at 95 C overnight. The reaction was quenched by water, and worked up under standard procedure. The residue was purified by flash column chromatography to give the title compound (2.1 g, yield: 78.9%). |
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