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Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
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Inaccessible (Haz class 6.1), Domestic | USD 80+ |
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Structure of 460-00-4
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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.
4.5
*For Research Use Only !
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Transition-Metal-Free Borylation of Aryl Bromide Using a Simple Diboron Source
Lim, Taeho ; Ryoo, Jeong Yup ; Han, Min Su ;
Abstract: In this study, we developed a simple transition-metal-free borylation reaction of aryl bromides. Bis-boronic acid (BBA), was used, and the borylation reaction was performed using a simple procedure at a mild temperature. Under mild conditions, aryl bromides were converted to arylboronic acids directly without any deprotection steps and purified by conversion to trifluoroborate salts. The functional group tolerance was considerably high. The mechanism study suggested that this borylation reaction proceeds via a radical pathway.
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Purchased from AmBeed: 20469-65-2 ; 13675-18-8 ; 2564-83-2 ; 872-31-1 ; 192863-35-7 ; 871231-46-8 ; 192863-36-8 ; 6793-92-6 ; 3972-65-4 ; 2398-37-0 ; 850623-47-1 ; 929626-22-2 ; 705254-31-5 ; 580-13-2 ; 2635-13-4 ; 623-12-1 ; 1015082-71-9 ; 52415-29-9 ; 23145-07-5 ; 619-42-1 ; 99-90-1 ; 192863-37-9 ; 578-57-4 ; 407-14-7 ; 216434-82-1 ; 668984-08-5 ; 423118-47-2 ; 108-85-0 ; 252726-24-2 ; 101-55-3 ; 850623-36-8 ; 4923-87-9 ; 1394827-04-3 ; 850623-42-6 ; 438553-44-7 ; 460-00-4 ; 1187951-62-7 ; 705254-34-8 ; 111-83-1 ; 111-83-1 ; 906007-40-7 ; 1443282-44-7 ; 1000160-76-8 ; 1111733-01-7 ; 99-90-1
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CAS No. : | 460-00-4 |
Formula : | C6H4BrF |
M.W : | 175.00 |
SMILES Code : | FC1=CC=C(Br)C=C1 |
MDL No. : | MFCD00000342 |
InChI Key : | AITNMTXHTIIIBB-UHFFFAOYSA-N |
Pubchem ID : | 9993 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225-H315-H319-H332-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Class: | 3 |
UN#: | 1993 |
Packing Group: | Ⅲ |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 34.1 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.08 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.01 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.48 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.93 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.42 |
Solubility | 0.0665 mg/ml ; 0.00038 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.75 |
Solubility | 0.313 mg/ml ; 0.00179 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.52 |
Solubility | 0.0522 mg/ml ; 0.000299 mol/l |
Class? Solubility class: Log S scale |
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 |
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 |
-5.18 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 |
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) |
1.29 |
* 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 |
---|---|---|
With sodium tetrahydroborate; magnesium; In tetrahydrofuran; ethanol; water; ethyl acetate; | Example 1 (4-Cyano-2-hydroxymethylphenyl)(4-fluorophenyl)methanol A solution of 4-fluorophenylmagnesium bromide, prepared from 4-fluorobromobenzene (605 g, 3.45 mole) and magnesium turnings (107 g, 4.4 mole) in dry THF (1200 mL), is added dropwise to a suspension of 5-cyanophthalid (500 g, 3.14 mole) in dry THF (3000 mL). The temperature is kept below 5° C. After the addition is complete, the reaction mixture is stirred the night over at room temperature. Ethanol (4500 mL) is added to the reaction mixture and NaBH4 (238 g, 6.30 mole) is added to the mixture in portions of 50 grams and is stirred the night over at room temperature. About 2/3 of the solvents is removed in vacuo and water (4000 mL) is added to the reaction mixture. The resulting solution is extracted with EtOAc (2*500 mL). Evaporation of the solvents leaves a crude title compound (780 g) as an oil which is deemed pure enough for further reaction. A pure sample is obtained after column chromatography on silica gel using EtOAc/n-Heptane (1/1) as eluent. The title compound is obtained as crystals after evaporation of the eluent. DSC onset: 116.5° C. 1H NMR (DMSO-db, 500 MHz): 4.42 (1H, dd J=13 Hz, J=5 Hz), 4.53 (1H, dd J=13 Hz, J=5 Hz), 5.45 (1H, t J=5 Hz), 5.98 (1H, d J=3 Hz), 6.14 (1H, d J=3 Hz), 7.15 (2H, J=10 Hz), 7.35 (2H, m), 7.74 (1H, d J=8.5 Hz), 7.77 (1H, d J=8.5 Hz), 7.83 (1H, s). Anal. calcd. for C15H12N1F1O2; C, 70.02; H, 4.71; N, 5.45. Found C, 70.01; H, 4.71; N, 5.51. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4-fluoro bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry 300ml tetrahydrofuran, is added to a suspension of 100g 5-cyanophthalide (0.628 moles) in 1000ml methylene dichloride at-6 to-2 C and worked up according to the method of Example 1, resulting in a thick semi-solid. This is triturated with 500ml of isopropyl alcohol (IPA) and cooled to0-5 C to provide 5-cyano-1- (4-fluorophenyl)-1, 3-dihydroisobenzofuran (2b) as a solid. This solid is filtered and washed with cold 50ml of IPA. Yield: 130-140g HPLC purity: 99.32percent | |
A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4-fluoro bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry 300ml tetrahydrofuran, is added to a suspension of 100g 5-cyanophthalide (0.628 moles) in 1000 ml toluene at-6to-2 C and worked-up as explained in Example 4 to provide a thick semi-solid. This is triturated with 500mi of isopropyl alcohol (IPA) and cooled to0-5 C to provide 2b as a solid. The solid is filtered and washed with 50ml of cold IPA. Dry weight :105-110g Purity by HPLC: 97.5percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4-fluoro bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry300moi tetrahydrofuran, is added to a suspension of 100g 5-cyanophthalide (0.628 moles) in1000ml methylene dichloride at-6to-2 C. After the reaction is completed, the reaction mass is quenched with100ml 20percent aqueous ammonium chloride solution. The organic layer is separated and diluted with100ml of methanol. Slowly, 12g of sodium borohydride (0.324moles) added over a period of one hour at below25 C, and the same temperature is maintained for 4-6 hours. The mixture is then cooled to 5-10 C, maintained for 2 hours and then the precipitated solid is filtered. The solid is washed with cold water and dried under vacuum below40 C to provide pure4-cyano-2-hydroxymethylphenyl- (4-fluorophenyl) methanol (5b). Yield: 115-120g HPLC purity: 99.2percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 4-fluorophenyl magnesium bromide (prepared from 153.3g 4- flouro bromobenzene, 25.3g magnesium turnings and Iodine (0.05gm) in dry 300ml tetrahydrofuran), was added to a suspension of lOOg 5-cyanophthalide in 900ml dichloromethane at -4 to -2°C. After the completion of the reaction a solution of 3- (N,N-dimethylamino)propyl magnesium chloride in toluene/THF mixture [generated in situ by reacting 175g 3-(N,N-dimethylamino)propyl chloride in 350ml toluene with 41.6gm magnesium turnings, 6.0 gin 4-bromofluorobenzene and Iodine in dry tetrahydrofuran] was added between 0 to -50C. The reaction mass was stirred for 3-4 hours. After completion of the reaction, the reaction mass was quenched with 20percent aqueous ammonium chloride solution. The organic layer was separated and washed with water. Organic layer was then extracted with 20percent acetic acid. The aqueous acid extract was cooled and pH was adjusted to 8.5 to 9.0 using liquor ammonia, and extracted with toluene 3 x 600ml. The toluene layer was washed with water, dried and then treated with carbon. Reaction mixture was filtered and subjected to salt formation to get Diol acid addition salts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With palladium diacetate; triethylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 1h;Sealed tube; | General procedure: A mixture of arylhalide (I, Br) (1 mmol), Weinreb amine hydrochloride(1.5 mmol), Pd(OAc)2 (5 mol %), xantphos (6 mol %), triethylamine (3 mmol), and cobalt carbonyl (0.3 mmol) in 1,4-dioxane was heated at 90 C for 1h in a septum-closed sealed tube. After cooling, the reaction mixture was concentrated in vacuum and the residue was extracted with ethylacetate and water. The ethylacetate layer was concentrated and the residue obtained was purified by flash column chromatography to get the desired product. Note: Carbon monoxide gas is highly toxic and should be handled by trained professionals in a well-ventilated fumehood with appropriate ventilation. In all the reactions, Co2(CO)8 was handled carefully in fumehoods using appropriate personal protective clothing and equipment. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.6% | With palladium diacetate; sodium t-butanolate; XPhos; In 1,4-dioxane; at 110℃; for 2h;Schlenk technique; Inert atmosphere; | An oven dried schlenk flask was evacuated and back filled with argon gas. The procedure was repeated for 3-4 times and cooled to room temperature. The dioxane (8 ml) was introduced with syringe and degassed for 20min with argon gas balloon. Then, the XPhos (267mg, 0.563mmol), Pd(OAc)2 (41mg, 0.187mmol) were added together and heated at 110 C for 1min. The reaction mixtures become clear red color solution. Then, the amine derivative 5 (250 mg, 1.87 mmol), 4-fluoro-bromobenzene (325mg, 1.87mmol) and sodium tert butoxide (540 mg, 5.63 mmol) were added together under argon atmosphere and the reaction mixture was heated at 110 C for 2h. The reaction mixture was poured in ethyl acetate (150 ml). The organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed and the residue was purified on silica gel column chromatography (100% EtOAc) to give the compound 33 (203 mg, 47.6%). 1H-NMR (400 MHz, CDCl3): delta = 8.63 (brs, 1H), 7.42 (dd, J = 4.8Hz, J = 13.6Hz, 2H), 7.06 (m, 2H), 6.58 (d, J = 8.4Hz, 1H), 6.41(brs, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | To a solution of 4-bromofluorobenzene (2 g, 11.4 mmol) in THF (20 mL) cooled to - 78 C, was added n-butyllithium dropwise (5.81 mL, 14.51 mmol) and the reaction mixture was stirred for 30 min. Then, a solution of tert- butyl 4-benzoylpiperidine-l- carboxylate (3 g, 10.37 mmol) in THF (15 mL) was added to the mixture which was stirred at -78 C for 2 hours. The mixture was allowed to warm up to room temperature, poured into a solution of sat. NH4C1 aqueous solution (50 mL) and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified peparative HPLC (Gemini NX column) to give the title compound (1.18 g, 29%) as colorless solid; MS: 312.1 (M-tBu-H20)+. |