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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. : | 3972-65-4 |
Formula : | C10H13Br |
M.W : | 213.11 |
SMILES Code : | CC(C1=CC=C(Br)C=C1)(C)C |
MDL No. : | MFCD00000108 |
InChI Key : | XHCAGOVGSDHHNP-UHFFFAOYSA-N |
Pubchem ID : | 77595 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
83% | With bis-triphenylphosphine-palladium(II) chloride; 1,1',1"-[benzene-1,3,5-triyltris(methylene)]tris[(octyl)-4-pyridin-4-ylpyridinium] hexafluorophosphate; tetrabutylammonium bis[(trifluoromethane)sulfonyl]imide; In N,N-dimethyl-formamide; at 60℃;Electrochemical reaction; | General procedure: In an undivided cellequipped with a Zn sacrificial anode (1.5 x 1.0 cm2) and a Pt cathode (1.5 x 1.0 cm2) was placed a DMF(3 mL) solution of 4-bromopropiophenone (4a, 0.053 g, 0.25 mmol), 1 (0.14 g, 7.6 x 10-2 mmol),[Bu4N+][Tf2N-] (0.16 g, 0.30 mmol), and a catalytic amount of PdCl2(PPh3)2 (0.0086 g, 1.2 x 10-2 mmol).The solution was electrolyzed under constant current conditions (10 mA) at 60 C until 2 F/mol-4a ofelectricity was passed. The reaction mixture was poured into 5% aq. HCl (12 mL). The mixture wasextracted with AcOEt (10 mL x 3). The combined organic layer was washed successively with waterand brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified bycolumn chromatography (SiO2, toluene/AcOEt = 10/1) to afford 4,4?-dipropanoylbiphenyl (5a, 0.030 g,0.11 mmol, 89%). |
68% | With bis-triphenylphosphine-palladium(II) chloride; 1,1'-dioctyl-4,4'-bipyridinium bis(trifluimide); tetrabutylammonium bis[(trifluoromethane)sulfonyl]imide; In 1-methyl-pyrrolidin-2-one; at 60℃;Electrochemical reaction; | A typical procedure of the electroreductive coupling of aryl bromide1 with catalytic amounts of [OctV2+][Tf2N]2 and Pd species isas follows. Into an undivided cell fitted with a Zn anode(1.5 1 cm2) and a Pt cathode (1.5 1 cm2) was added a DMF(3 mL) solution of 4-bromopropiophenone (1a, 0.25 mmol),[Bu4N+][Tf2N] (0.3 mmol), [OctV2+][Tf2N]2 (0.075 mmol,30 mol %), and PdCl2(PPh3)2 (0.0125 mmol, 5 mol %). The wholemixture was electrolyzed at 60 C under constant current(10 mA) conditions until 2 F/mol-1a of electricity was passed.The reaction mixture was poured into 5% aq HCl and extractedwith AcOEt. Purification by column chromatography (SiO2, toluene/AcOEt = 10/1) afforded 4,40-dipropanoylbiphenyl (2a) in 94%yield |
64% | With palladium diacetate; bis(tri-n-butyltin); cesium fluoride; tricyclohexylphosphine; In neat (no solvent); at 110℃; for 24h; | A screw-cap vial equipped with a magnetic stir bar was charged with aryl halide (1 mmol), hexa-n-butylditin (0.5 mmol),palladium acetate (0.01 mmol) and tricyclohexylphosphine (0.02 mmol),followed by anhydrous cesium fluoride (1.5 mmol). The resulting mixture was manually homogenized with a magnet. A vial was transferred to a preheated oil bath (110 C). After 24 h, the mixture was cooled, dissolved in CH2Cl2-H2O mixture (1:1), the organic phase was separated, the solvent was evaporated in vacuo and the product was isolated by flash chromatography on a silica gel by elution with hexane-CH2Cl2 mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; n-butyllithium;sodium carbonate; tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; diethyl ether; toluene; | Step (a) Preparation of 4-(4'-tert-Butyl-biphenyl-4-yl)-4-oxo-butyric acid methyl ester To a stirred solution of 4-tert-butyl-bromobenzene (21.3 g, 0.0999 mol) in THF (30 mL) at -78 C. under nitrogen was added dropwise a 2.1 M solution of n-butyl lithium in hexanes (45 mL, 0.095 mol), and the mixture was stirred for 1.5 hours. To the mixture was added dropwise neat trimethylborate (10.2 mL, 0.090 mol), and the mixture was allowed to slowly warm to room temperature. The mixture was stirred overnight, then quenched by dropwise addition of 1.0 M aqueous hydrochloric acid. Brine was added, and the organic layer was dried (Na2SO4) and rotary evaporated. The residue was crystallized from n-heptane to give 4.65 g of crude 4-tert-butyl-phenyl-boronic acid as white needles. This material was used directly in the next reaction without further characterization. Thus, in a manner similar to Example 12, Step (b), 4-tert-butyl-phenyl-boronic acid (0.4287 g, 0.00241 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (0.5443 g, 0.00200 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.0472 g, 0.0000408 mol) and 2.0 M aqueous sodium carbonate (2.4 mL, 0.0048 mol) in toluene (5 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluding with toluene then chloroform, 0.50 g. The material was dissolved in diethyl ether, washed with 0.10 M aqueous sodium hydroxide, water and brine. The organics were dried (K2CO3), and rotary evaporated to give 0.45 g of 4-(4'-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 58-62 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; 1,2-dimethoxyethane; | EXAMPLE 27 Synthesis of 4-t-butylbiphenyl using K3PO4 as Base with 0.1 mol percent Pd An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium phosphate (425 mg, 2.0 mmol). The tube was evacuated and backfilled with argon, and DME (1.5 mL) and 1-bromo-4-t-butylbenzene (0.17 mL, 1.0 mmol) were added through a rubber septum. A separate flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-(di-tert-butylphosphino)biphenyl (4.5 mmol, 0.015 mmol), and DME (1 mL). The mixture was stirred for 1 minute at room temperature, then 100 muL of this solution (0.1 mol percent Pd, 0.15 mol percent 2-(di-tert-butylphosphino)biphenyl) was added to the Schlenk tube followed by additional THF (1.5 mL). The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes, then heated to 80° C. with stirring until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 199 mg 95percent) of a glassy solid. | |
199 mg (95%) | tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; 1,2-dimethoxyethane; | Example 27 Synthesis of 4-t-butylbiphenyl using K3PO4 as base with 0.1 mol percent Pd An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium phosphate (425 mg, 2.0 mmol). The tube was evacuated and backfilled with argon, and DME (1.5 mL) and 1-bromo-4-t-butylbenzene (0.17 mL, 1.0 mmol) were added through a rubber septum. A separate flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-(di-tert-butylphosphino)biphenyl (4.5 mmol, 0.015 mmol), and DME (1 mL). The mixture was stirred for 1 minute at room temperature, then 100 muL of this solution (0.1 mol percent Pd, 0.15 mol percent 2-(di-tert-butylphosphino)biphenyl) was added to the Schlenk tube followed by additional THF (1.5 mL). The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes, then heated to 80° C. with stirring until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 199 mg (95percent) of a glassy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
202 mg (96%) | With cesium fluoride;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; | EXAMPLE 28 Synthesis of 4-t-butylbiphenyl using CsF as Base with 0.05 mol percent Pd An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with phenylboron dihydroxide (183 mg, 1.5 mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1.5 mL) and 1-bromo-4-t-butylbenzene (0.17 mL, 1.0 mmol) were added through a rubber septum. A separate flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-(di-tert-butylphosphino)biphenyl (4.5 mmol, 0.015 mmol), and THF (1 mL). The mixture was stirred for 1 minute at room temperature, then 50 muL of this solution (0.05 mol percent Pd, 0.075 mol percent 2-(di-tert-butylphosphino)biphenyl) was added to the Schlenk tube followed by additional THF (1.5 mL). The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes, then heated to 80° C. with stirring until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 202 mg (96percent) of a glassy solid. |
202 mg (96%) | With cesium fluoride;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; | Example 28 Synthesis of 4-t-butylbiphenyl using CsF as base with 0.05 mol percent Pd An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with phenylboron dihydroxide (183 mg, 1.5 mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1.5 mL) and 1-bromo-4-t-butylbenzene (0.17 mL, 1.0 mmol) were added through a rubber septum. A separate flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-(di-tert-butylphosphino)biphenyl (4.5 mmol, 0.015 mmol), and THF (1 mL). The mixture was stirred for 1 minute at room temperature, then 50 muL of this solution (0.05 mol percent Pd, 0.075 mol percent 2-(di-tert-butylphosphino)biphenyl) was added to the Schlenk tube followed by additional THF (1.5 mL). The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes, then heated to 80° C. with stirring until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 202 mg (96percent) of a glassy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrogen; sodium t-butanolate; In toluene; | Example 5 Preparation of N-(4-tert-butylphenyl)-<strong>[42933-43-7]2,3-dihydro-1-benzofuran-5-amine</strong> To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added <strong>[42933-43-7]2,3-dihydro-1-benzofuran-5-amine</strong> (11.6 grams, 85.8 mmoles, prepared as in Example 23 of U.S. Pat. No. 20040029932), 4-tert-butyl bromobenzene (18.1 grams, 85 mmoles), tris(dibenzylideneacetone)dipalladium (0) (1.6 grams, 1.7 mmoles), rac-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (2.1 grams, 3.4 mmoles), sodium tert-butoxide (16.4 grams, 0.17 moles) and anhydrous toluene (100 mL). The contents of the flask were refluxed for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (150 mL). The combined organic layers were concentrated in vacuo to yield a dark solid. The solid was chromatographed on silica gel, eluding with hexane/ethyl acetate (20:1) to afford 10 grams of the desired product as a white solid. 1H NMR (CDCl3) delta 7.25 (d, 2H), 6.95 (s, 1H), 6.85 (d, 3H), 6.7 (d, 1H), 5.4 (bs, 1H), 4.5 (t, 2H), 3.15 (t, 2H), 1.3 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 72h;Heating / reflux; | Example 5; Preparation of N-(4-tert-butylphenyl)-<strong>[42933-43-7]2,3-dihydro-1-benzofuran-5-amine</strong>; [Show Image] To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added <strong>[42933-43-7]2,3-dihydro-1-benzofuran-5-amine</strong> (11.6 grams, 85.8 mmoles, prepared as in Example 23 of U.S. Pat. No. 20040029932), 4-tert-butyl bromobenzene (18.1 grams, 85 mmoles), tris(dibenzylideneacetone)dipalladium (0) (1.6 grams, 1.7 mmoles), rac-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (2.1 grams, 3.4 mmoles), sodium tert-butoxide (16.4 grams, 0.17 moles) and anhydrous toluene (100 mL). The contents of the flask were refluxed for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (150 mL). The combined organic layers were concentrated in vacuo to yield a dark solid. The solid was chromatographed on silica gel, eluting with hexane/ethyl acetate (20:1) to afford 10 grams of the desired product as a white solid. 1H NMR (CDCl3) delta 7.25 (d, 2H), 6.95 (s, 1H), 6.85 (d, 3H), 6.7 (d, 1H), 5.4 (bs, 1H), 4.5 (t, 2H), 3.15 (t, 2H), 1.3 (s, 9H). | |
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 72h;Heating / reflux; | To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added <strong>[42933-43-7]2,3-dihydro-1-benzofuran-5-amine</strong> (11.6 grams, 85.8 mmoles, prepared as in Example 23 of U.S. Pat. No. 20040029932), 4-tert-butyl bromobenzene (18.1 grams, 85 mmoles), tris(dibenzylideneacetone)dipalladium (0) (1.6 grams, 1.7 mmoles), rac-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (2.1 grams, 3.4 mmoles), sodium tert-butoxide (16.4 grams, 0.17 moles) and anhydrous toluene (100 mL). The contents of the flask were refluxed for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (150 mL). The combined organic layers were concentrated in vacuo to yield a dark solid. The solid was chromatographed on silica gel, eluting with hexane/ethyl acetate (20:1) to afford 10 grams of the desired product as a white solid. 1H NMR (CDCl3) delta 7.25 (d, 2H), 6.95 (s, 1H), 6.85 (d, 3H), 6.7 (d, 1H), 5.4 (bs, 1H), 4.5 (t, 2H), 3.15 (t, 2H), 1.3 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In 5,5-dimethyl-1,3-cyclohexadiene; for 6h;Reflux; Inert atmosphere; | (Synthesis of Exemplary Compound (A-1)) (0433) Compound (A-1) in which D1 in Formula (I) is a compound represented by Formula (III) may be prepared by the following reaction scheme. 2-iso-propynylaniline (4.10 g, 30.8 mmol), bis(dibenzylidene)palladium (Pd(dba)2) (463 mg, 0.700 mmol), (±)-BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (653 mg, 1.05 mmol), sodium-tert-butoxide (4.03 g, 42.0 mmol) and 1-bromo-4-tert-butylbenzene (5.97 g, 28.0 mmol) were dissolved in 50 ml of xylene, and reacted by boiling under reflux for 6 hours under a nitrogen atmosphere to obtain Compound 1 in 90% yield. Compound 1 (6.70 g, 25.2 mmol) was added to a mixed solvent of 37 ml of acetic acid and 7.5 ml of hydrochloric acid, and followed by stirring at 60 C. for 30 minutes to obtain Compound 2 in 82% yield. Compound 2 (1.30 g, 4.90 mmol), palladium acetate ((Pd(OAc)2)) (55.0 mg, 0.245 mmol), tri(t-butyl)phosphine (149 mg, 7.35 mmol), cesium carbonate (3.19 g, 9.80 mmol) and 1-bromo-4-tert-butylbenzene (1.15 g, 5.39 mmol) were dissolved in 15 ml of xylene, and reacted by boiling under reflux for 6 hours under a nitrogen atmosphere to obtain Compound 3 in 70% yield. Compound 3 (1.36 g, 3.43 mmol) was added to 25 ml of DMF (N,N-dimethylformamide) with stirring under a nitrogen atmosphere, and phosphoryl bromide (1.97 g, 6.86 mmol) was added in small portions. Stirring was performed at 100 C. for 1 hour to obtain Compound 4 in 68% yield. Compound 4 (750 mg, 1.76 mmol) and benzindandione (380 mg, 1.94 mmol) were added to 9 ml of acetic acid under a nitrogen atmosphere, and refluxed for 3 hours. After allowing to cool, suction filtration was performed, and recrystallization was performed with N,N-dimethylacetamide. Suction filtration was performed to obtain Compound (A-1) in 57% yield. The compound was identified by 1H-NMR. (0436) 1H-NMR (400 M Hz, in DMSO-d6): δ (ppm)=1.29 (s, 9H), 1.43 (s, 9H), 1.80 (s, 6H), 6.11 (d, J=8.6 Hz, 1H), 6.20 (d, J=8.7 Hz, 1H), 7.09 (dd, J=8.7, 1.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.58 (s, 1H), 7.74-7.78 (m, 4H), 7.84 (s, 1H), 8.13-8.17 (m, 1H), 8.28-8.31 (m, 2H), 8.56 (d, J=15.4 Hz, 2H), 36 (s, 1H). m.p.=341 C., λmax 549 nm (in CHCl3) (ε=66000 mol-1·l·cm-1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With C21H19N2(1+)*Br(1-); palladium diacetate; potassium carbonate; In toluene; at 70℃; for 3h; | General procedure: A reaction tube was charged with Pd(OAc)2 (1.34 mg, 0.006 mmol), imidazolium salt (0.0072 mmol), K2CO3 (62 mg, 0.45 mmol), and ArB(OH)2 (0.45 mmol). To the reaction tube were added toluene (2.0 mL) and aryl bromide (0.3 mmol). The mixture was stirred at 70 °C in the presence of air for 3 hours. The mixture was cooled to room temperature and directly purified through silica gel column chromatography to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.47 g | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 12h; | To a solution of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (2.39 g) in N, N-dimethylformamide (24 mL) was added 1-bromo-4-tert-butylbenzene (4.40 mL), N, N ' -Dimethyl ethylenediamine (0.918 mL), copper iodide (I) (3.25 g) and cesium carbonate (11.1 g) were added and stirred at 110 ° C. (oil bath temperature) for 12 hours. After filtering the reaction solution with Celite (registered trademark), water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10 to 80:20) to give the title compound (2.47 g) as a pale yellow oil. |