Structure of 1564-64-3
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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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C (sp3)-heteroatom bond formation by iron-catalyzed soft couplings
Semenya, Julius ; Yang, Yuanjie ; Lee, Hye Joon ; Giannantonio, Kimberly A ; Manduva, Rikhil ; Picazo, Elias
Abstract: Carbon-heteroatom bonds are of great importance due to their prevalence in pharmaceuticals, agrochemicals, materials, and natural products. Despite the effective use of metal-catalyzed crosscoupling reactions between sp2-hybridized organohalides and soft heteroatomic nucleophiles for carbon-heteroatom bond formation, the use of sp3-hybridized organohalides remain limited and the coupling with thiols remains elusive. Here, we report the coupling of sp3-hybridized benzyl or tertiary halides with soft thiol nucleophiles catalyzed by iron and extend the utility to alcohol and amine nucleophiles. The reaction is broad in substrate scope for both coupling partners and applicable in the construction of congested tri- and tetrasubstituted carbon centers as well as β-quaternary heteroatomic products. The synthetic utility is further emphasized by gram-scale synthesis and rapid herbicide library synthesis. Overall, we provide an efficient method to prepare pharmaceutically and materially relevant carbon-heteroatom bonds by expanding iron-catalyzed cross-coupling reactions to the coupling of sp3-hybridized organohalides with soft nucleophiles.
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Purchased from AmBeed: 76041-72-0 ; 2564-83-2 ; 73018-10-7 ; 63295-48-7 ; 1564-64-3 ; 65130-46-3 ; 15687-27-1 ; 91-60-1 ; 59163-91-6 ; 15570-12-4 ; 56673-34-8 ; 7217-59-6 ; 696-63-9
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CAS No. : | 1564-64-3 |
Formula : | C14H9Br |
M.W : | 257.13 |
SMILES Code : | BrC1=C2C=CC=CC2=CC3=CC=CC=C13 |
MDL No. : | MFCD00001243 |
InChI Key : | ZIRVQSRSPDUEOJ-UHFFFAOYSA-N |
Pubchem ID : | 74062 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P201-P264-P202-P261-P271-P280-P302+P352-P308+P313-P304+P340-P305+P351+P338-P332+P313-P362+P364-P403+P233-P501 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 14 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 69.15 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.73 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
5.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.76 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.9 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.72 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
4.47 |
Log S (ESOL):? ESOL: Topological method implemented from |
-5.42 |
Solubility | 0.000978 mg/ml ; 0.0000038 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.98 |
Solubility | 0.0027 mg/ml ; 0.0000105 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.6 |
Solubility | 0.000064 mg/ml ; 0.000000249 mol/l |
Class? Solubility class: Log S scale |
Poorly 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) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
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 |
-4.16 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 |
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) |
1.46 |
* 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 |
---|---|---|
86% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos; In toluene; at 100 - 110℃; for 2h;Inert atmosphere; | (1) To mechanical agitation, thermometer, After replacing the three-port reaction flask in the condenser with nitrogen, Add intermediate 24a (100mmol) in sequence, Raw material 24b (95mmol), 300ml toluene, heated to reflux for 0.5h, Cool down to 70 - 80 C, Slowly add sodium tert-butoxide (150mmol), Pd2 (dba) 3 (0.25mmol), xphos (0.5mmol), After the system is stable, it is heated to 100 - 110 C for 2 hours. Reduce the temperature to 25 - 30 C, add 200ml of water, stir and separate with 100ml of toluene, and extract the aqueous phase once with 200ml of toluene. Separate the liquid, combine the organic phase, add 7g of anhydrous sodium sulfate to the organic phase, stir and dry, filter The organic phase is concentrated (-0.08-0.09MPa, 55-60 C ) so that Recrystallize with 60ml toluene, filter, 82 mmol of intermediate 24c was obtained with a yield of 86%. |
70% | With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In toluene; at 100℃; for 72h;Inert atmosphere; Sealed tube; | An oven-dried pressure tube was cooled under nitrogen and charged with 9-bromanthracene (0.5 g, 1.9 mmol), distilled aniline (0.26 mL, 2.9 mmol), NaOtBu (0.44 g, 3.8 mmol), Pd(OAc)2 (22 mg, 5 mol%) and P(tBu)3 (23 uL, 0.1 mmol). To this was added dry toluene (10 mL). The pressure tube was sealed under nitrogen and stirred at 100 C for 72 h. After 72 h, the pressure tube was cooled to rt and toluene was removed in vacuo. Subsequently, the reaction was quenched with water and the organic contents were extracted with chloroform. The combined extract was dried over anhyd Na2SO4 and filtered. The solvent was removed in vacuo and the crude product was subjected to silica gel column chromatography using CHCl3/pet.ether (5:95) as an eluent to yield pure 9-(N-phenylamino)anthracene as yellow crystalline solid (0.36 g, 70% yield); mp 145 C; IR (neat film) cm1 3392, 1601, 1499, 1421, 1355, 1307; 1H NMR (CDCl3, 500 MHz) d 5.99 (s,1H), 6.59 (d, J = 8.0 Hz, 2H), 6.78 (t, J = 6.8 Hz, 1H), 7.14(t, J = 7.4 Hz, 2H), 7.44-7.48 (m, 4H), 8.05 (d, J = 8.6 Hz,2H), 8.19 (d, J = 8.6 Hz, 2H), 8.41 (s, 1H); 13C NMR (CDCl3, 125 MHz) d 113.8, 118.4, 123.8, 125.3, 125.4, 125.8,128.7, 129.0, 129.2, 132.2, 132.4, 147.9; EI-MS+ m/z Calcdfor C20H15N 269.1204 [M+], found 269.1206. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; for 12h;Inert atmosphere; Reflux; | d. Preparation of Intermediate IInto a RBF (5000 mL) was added 9-bromoanthracene (100 g, 0.389 mol), 4-(Naphthalene-1-yl) Phenyl boronic acid (116 g, 0.469 mol), followed by the addition of toluene (3000 mL). The mixture was purged with N2 for 10 min. Then Na2CO3 (124 g, 1.167 mole) dissolved in the water (600 mL) was added. The mixture was continued to be purged with N2 for 10 min. A catalytic amount of Pd(PPh3)4 (2.3 g, 1.95 mmole) was added. The mixture was refluxed under N2 for 12 h. Cooled down the reaction mixture to 40 C., filtered, separated off water layer, and concentrate the organic phase to a final volume (150 ml) to obtain the solid of intermediate I (131 g, yield: 92%). C30H2O: El, MS m/z (%): 380 (100, M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.3g | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); for 8h;Inert atmosphere; Reflux; | Under the nitrogen atmosphere, triphenylen-2-ylboronic acid (5.6 g), 9-bromoanthracene (3.5 g), (Pd(PPh3)4) (0.5 g), potassium phosphate (5.8 g), and a mixture solvent of pseudo cumene, t-butyl alcohol, and water (48 ml) (pseudo cumene/t-butyl alcohol/water = 10/1/1 (volume ratio)) were added to a flask and then refluxed for 8 hours. After adding water, the precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol and purified by silica gel column chromatography (solvent: toluene). After re-crystallization with a mixture solution of toluene/ethyl acetate, 2-(anthracen-9-yl)triphenylene (3.3 g) was obtained as an eleventh intermediate compound. The scheme is represented in the following 'Reaction 21'. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.8% | With palladium diacetate; triethylamine; triphenylphosphine; In toluene; at 20 - 80℃; for 60h;Inert atmosphere; | PA was synthesized as previously described [31]. Typically, 633 mg (1 mmol) OV-POSS was added in 50 mL reaction tube with 514 mg (2 mmol) 9-bromoanthracene, 22.4 mg (0.1 mmol) palladium acetate and 100.4 mg (0.4 mmol) triphenylphosphine. Under an inert atmosphere of nitrogen, 20 mL toluene and 5 mL triethylamine was added and stirred at room temperature for 12 h, then the reaction continued at 80 °C for 48 h. The obtained white precipitate was filtered through 1 cm celite. The filtrate was dissolved with a small amount of toluene and precipitated in 200 mL methanol. This procedure was repeated for 3 times to give a yellow powder at a yield of 10.8percent. FTIR (KBr), n (cm1): 3059, 3023, 2984, 2958 (SieCH]CH2), 3048 (AreH), 1623, 1442 (Ar), 1602 (SieCH]CH2), 1123 (SieOeSi),732(AreH). 2D-NMR HMQC: 1H NMR (400 MHz, CDCl3), d, (ppm) 6.08 (br, SieCH]CH2), 7.23, 7.79, 8.18 (br, AreH); 13C NMR (100.13 MHz, CDCl3), d, (ppm): 125.46, 128.47 (AreH, SieCH] CHeAr), 137.14 (SieCH]CH2). 29Si-NMR (79.49 MHz, CDCl3), d, (ppm): 79.59 (SieCH]CH2), 78.86 (SieCH]CHeAr). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 6h;Inert atmosphere; Reflux; | 9-bromo-anthracene (5.14g, 0.02mol) to a three-necked flask, BnImBA (6.91g, 0.022mol), aqueous potassium carbonate (48.3g, 0.06mol), 100ml of toluene, 50ml of ethanol; under nitrogen, was added with stirring Pd (PPh3)4(0.23g, 0.2mmol), after the replacement with nitrogen, the reaction was refluxed for 6 hours; after completion of the reaction, was cooled to room temperature, the layers were separated and the organic phase washed with saturated sodium chloride until neutral, dried over anhydrous sodium sulfate and filtered to give a red brown liquid ; The solvent was removed by rotary evaporation, silica gel column, eluent VPetroleum ether: VDichloromethane= 1: 3 purification separation to give a pale yellow powder, yield 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.9 g | 9-Bromoanthracene (25.0 g), Bispinacolatodiboron (27.0 g),Pd (dba) 2 (1.7 g), tricyclohexylphosphine (1.6 g), potassium acetate (19.0 g)Potassium carbonate (14.0 g) and cyclopentyl methyl ether (200 ml) were addedThe resulting flask was heated and stirred at a reflux temperature for 10 hours.After cooling to room temperature, 27.0 g of 4- (4-bromophenyl) pyridine, 2.2 g of Pd (PPh3) 4 and 1,2,4-trimethylbenzene (200 ml)And the mixture was heated and stirred at a reflux temperature for further 2 hours.The reaction solution was cooled to room temperature, and the desired product was extracted with chlorobenzene.To this chlorobenzene solution, a solution obtained by dissolving ethylenediaminetetraacetic acid · tetrasodium salt dihydrate equivalent to approximately equimolar amount with respect to the aimed compound in an appropriate amount of water (hereinafter, referred to as EDTA · 4Na aqueous solution ) Was added, and the solution was separated.The solvent was distilled off under reduced pressure, and the precipitated solid was washed with methanol. Further, it was dissolved again in chlorobenzene and purified by activated alumina column chromatography (eluent: chlorobenzene / ethyl acetate mixed solvent).At this time, with reference to the method described in "Organic Chemistry Experiment Guide (1) -Material Handling Method and Separation and Refinement Method" published by Kagaku Dojin Publishing Co., Ltd., page 94, the ratio of ethyl acetate in the developing solution was gradually increased to elute the target substance .The solvent was distilled off under reduced pressure, and the residue was washed with methanol to obtain 4- (4- (anthracen-9-yl) phenyl) pyridine (15.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.7% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 8h;Inert atmosphere; Reflux; | Under nitrogen protection,With mechanical stirring,9-bromoindole (25.9 g, 10 mmol),<strong>[867044-33-5][4-(2-phenyl-1H-benzimidazol-1-yl)phenyl]boronic acid</strong> (1.1 eq.),Potassium carbonate 2eq,Pd(Pph3)4 (1%),Toluene 500ml + ethanol 100ml + 100ml water,Turn on the agitation,Heated to reflux,Reaction 8h.Organic phase silica gel column chromatography,concentrate,Recrystallization from toluene gave yellow powder M1 (4.2 g, 93.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94%; 2% | With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; acetic acid; for 0.7h;Irradiation; Inert atmosphere; | General procedure: Into a flask charged with the respective alpha-haloketone 2 (1 mmol) and ethidine (Hantzsch's ester, 1a; 1.2 mmol), was added the solvent as per Tables 2-4 (2.5 mL). The flask was then attached to a balloon filled with N2 and irradiated with 3 W blue LED at a distance of 5 cm. The workup was followed when TLC showed that ethidine or the haloketone was consumed. When AcOH was used as the solvent, the reaction was worked up as follows: the reaction mixture was partitioned between EtOAc (40 mL) and H2O (10 mL), then the organic phase was washed with sat. aq NaHCO3 (3 15 mL) and brine (15 mL), and dried (anhyd Na2SO4). After concentration under reduced pressure, the residue was subjected to flash chromatography for purification eluting with petroleum ether (PE) and CH2Cl2. When aprotic polar solvents were used, the reaction mixture was diluted with EtOAc (40 mL) and the organic layer was washed with H2O (3 15 mL) and brine (15 mL), and dried (anhyd Na2SO4). When volatile solvents were used, the mixture was concentrated under reduced pressure and the residue was subjected to flash chromatography for purification. |