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CAS No. : | 4408-64-4 | MDL No. : | MFCD00004284 |
Formula : | C5H9NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XWSGEVNYFYKXCP-UHFFFAOYSA-N |
M.W : | 147.13 | Pubchem ID : | 20441 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.6 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 32.59 |
TPSA : | 77.84 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.55 cm/s |
Log Po/w (iLOGP) : | 0.79 |
Log Po/w (XLOGP3) : | -3.32 |
Log Po/w (WLOGP) : | -0.91 |
Log Po/w (MLOGP) : | -0.96 |
Log Po/w (SILICOS-IT) : | -1.39 |
Consensus Log Po/w : | -1.16 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | 1.6 |
Solubility : | 5900.0 mg/ml ; 40.1 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 2.26 |
Solubility : | 26700.0 mg/ml ; 182.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.86 |
Solubility : | 1070.0 mg/ml ; 7.24 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.3 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
55% | Stage #1: With Trimethyl borate In tetrahydrofuran at -78 - 23℃; for 5.5 h; Inert atmosphere Stage #2: at 105 - 115℃; for 2.16667 h; Inert atmosphere |
To a 3 L three-neck round bottom flask equipped with a stir bar were added B(OMe)3 (94 mL, 840 mmol) and THF (600 mL). The solution was cooled to 78 °C. Vinylmagnesium bromide (1.0 M in THF, 800 mL, 800 mmol) was added dropwise via cannula over 2 h 45 min. The resulting solution was stirred at 78 °C for 15 min, followed by stirring at 23 °C for 2 h 30 min. In a separate 2 L three neckround bottom flask equipped with a stir bar, internal thermometer, and distillation apparatus were added dry MIDA (235.0 g, 1.6 mol) and DMSO (600 mL). The solution was heated with an oil bath to an internal temperature of 110-115 °C. The borate suspension was added dropwise to the hot MIDA solution via a Teflon cannula dropwise over 2 h 10 min, keeping the internal temperature between 105 and 115 °C. After full addition of the borate solution, the reaction solution was cooled to 23 °C. The resulting solution was transferred to a separatory funnel containing H2O (1 L), brine (1 L), EtOAc (1.5 L), and acetone (1 L). The mixture was shaken and the aqueous layer was removed and extracted with EtOAc/acetone (2:1, 2600 mL). The combined organic layers were washed with H2O (2500 mL). The combined water washes were back extracted with EtOAc/acetone (2:1, 2300 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was suspended in 300 mL acetone and 4 L Et2O was added to precipitate the product. The resulting solid was collected by vacuum filtration to yield vinyl MIDA boronate 1 as a white solid (81.2 g, 55percent). Spectral data for 1 were consistent with those previously reported from our laboratories.13 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | at 95 - 115℃; | Example 4Preparation of Vinyl MIDA Boronate from Corresponding Grignard ReagentTo a dry 500 mL Schlenk flask equipped with a stir bar was added THF (100 mL) and B(OMe)3 (11.7 mL, 105 mmol). The solution was cooled via a -78° C. cold bath. To the solution was added via cannula over 5 min. vinylmagnesium bromide as a solution in THF (1.0 M, 100 mL, 100 mmol). The resulting mixture was stirred for 2 h, then the cold bath was removed and the mixture was allowed to warm to room temperature with stirring for 2 h. The beige mixture was transferred to a 250 mL pressure-equalizing addition funnel. A 3-neck 500 mL round bottom flask equipped with a stir bar was charged with DMSO (100 mL), N-methyliminodiacetic acid (29.5 g, 200 mmol) and toluene (50 mL). To the necks of the round bottom were fitted the addition funnel, a thermometer, and a std. distillation apparatus. The mixture was heated to an internal temperature of 115° C. upon which the THF mixture was added via the addition funnel at a rate to maintain an internal temperature between 95-110° C. During this time the THF is distilled away from the hot DMSO mixture. Upon completion of the addition and after the internal temperature had risen to 120° C. the distillation pot was allowed to cool to room temperature.The DMSO mixture was diluted with acetone (300 mL) and the resulting mixture was filtered through a pad of Celite. The collected solids were extracted with acetone (100 mL) and the combined filtrate was concentrated in vacuo to afford a DMSO solution. The DMSO solution was distilled to near dryness (1 Torr, 100° C.). The remaining solids were dissolved in acetone:water (100 mL:100 mL) and were transferred to a 1000 mL separatory funnel. The solution was diluted with brine (100 mL) and EtOAc (200 mL). The mixture was shaken and the phases were separated. The aq. phase was twice extracted with acetone:EtOAc (100 mL:200 mL). The combined organics were washed with brine (3.x.100 mL). The combined brine washes were back-extracted with EtOAc (100 mL). The combined organics were dried over MgSO4, filtered, then concentrated in vacuo to afford an off-white solid which was then recrystallized from acetone (100 mL) diluted with Et2O (2000 mL) to afford the product 7c as an off-white solid (9.95 g, 54percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: at 20℃; for 13 h; Stage #2: at 23℃; for 0.0833333 h; |
Vinyl-MIDA-Boronate (306); To a dry 6 mL vial fitted with a septum cap, equipped with a stir bar, and placed under Ar atmosphere was added BBr3 in CH2Cl2 (1.3 mL, 1.0 M, 1.3 mmol). To the stirred solution was added vinyltrimethylsilane (140 μL, 0.983 mmol). The solution was stirred at room temperature for 13 h. Separately, a dry 25 mL round bottom flask equipped with a stir bar, fitted with a rubber septum, and placed under Ar atm. was charged with sodium N-methyliminodiacetate (478 mg, 2.50 mmol) and DMSO (4 mL). To this stirred suspension was added dropwise by syringe the crude vinylboron dibromide solution. The mixture was stirred for 5 min. The mixture was concentrated in vacuo. The residue was adsorbed onto Florisil gel from an acetone suspension. The resulting powder was dry-loaded onto a silica gel column slurry packed in Et2O. The column was flushed with Et2O (app. 200 mL), then was eluted with Et2O:MeCN (3:1) to afford 306 as a colorless solid, 88 mg (48percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride In water at 0 - 70℃; for 12h; Inert atmosphere; | Preparation of Diethyl(Imino-Methyl)Diacetate Diethyl(imino-methyl)diacetate (reference AW4) is a compound represented by structural formula (I) in which x=y=1, R1 and R2 each represent an ethyl group and R4 represents methyl. This compound was prepared as follows. A solution of methylimino diacetic acid (20.0 g, 0.136 mol., 1.0 eq.) in dry ethanol (200 ml) was cooled to 0° C. Concentrated HCl (9.93 g, 0.272 mol., 2.0 eq.) was added drop wise with stirring under nitrogen. The reaction mixture was refluxed at 70° C. for 12 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated. Reaction mass was extracted with ethyl acetate (2×250 ml). The organic phase was washed with water (1×250 ml), NaHCO3 (1×250 ml) & brine (1×250 ml). The organic layer was dried over Na2SO4, and concentrated under vacuum. The crude product was purified through column chromatography using 0.5% methanol in CHCl3 as eluent system to get the required product (80%). It was characterized by 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With pyridine; acetic anhydride at 70℃; for 1.5h; Reflux; | 6 Example 6 Preparation of MIDA Anhydride A round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with N-methyliminodiacetic acid (25.0 g, 170 mmol, 1.0 equiv), acetic anhydride (85 mL, ~850 mmol, ~5 equiv.), and pyridine (274.9 μL, 3.4 mmol, 0.02 equiv). The flask was capped with a rubber septum which was pierced with an 18 gauge needle (alternatively a reflux condenser could be used). The reaction was lowered into a preheated 70° C. oil bath and stirred until the mixture became clear and dark orange (about 1.5 h). The acetic acid, pyridine, and remaining acetic anhydride were then removed by vacuum distillation (37° C. to 42° C. at 30 Torr). The resulting brown-black liquid was azeotroped three times with toluene (50 mL) to remove residual acetic acid and then transferred to an Erlenmeyer flask. To this flask was added enough diethyl ether to dissolve the crude N-methyl morpholine dione product (~400 mL). The resulting mixture was filtered to remove a black-brown precipitate, and the filtrate was concentrated in vacuo. The resulting pale yellow solid was then recrystallized from a minimum amount of hot diethyl ether to yield N-methyl morpholine dione (MIDA anhydride; 16.9 g, 131 mmol, 77%) as an off-white crystalline solid. |
48% | With pyridine; acetic anhydride at 70℃; for 24h; | |
In acetic anhydride Heating; |
With acetic anhydride for 0.333333h; Heating / reflux; | 36 A stirred mixture of N-methyliminodiacetic acid (0.06 g, 0.4 mmol) and acetic anhydride (1 ml) was heated under reflux under nitrogen for 20 minutes, until a clear solution was obtained. The excess of acetic anhydride and the acetic acid produced in the reaction were removed in vacuo and the residual 4-methylmorpholine-2,6-dione was dissolved in toluene (7 ml) and used without purification. | |
With acetic anhydride for 0.5h; Reflux; | ||
With acetic anhydride at 165℃; for 0.5h; | 35.1 Example 35 The obtained crude product was dissolved in THF (10 mL), and p-aminobenzonitrile (401 mg, 3.40 mmol) was added thereto. The mixture was heated with reflux for 22 hr, and concentrated under reduced pressure to give 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)(methyl)amino)acetic acid (467 mg, 56%) as a pale-brown powder. 1H-NMR(300MHz, DMSO-d6) :δ2.42(3H,s), 3.41(4H,s), 7.76-7.85(4H,m), 10.30(1H,s) | |
With acetic anhydride; trifluoroacetic anhydride at 20℃; for 4h; | 5.4.2. General procedure A for anhydride opening by amines 1) Obtention of anhydrides: iminodiacetic acid analogue (5 mmol) was dissolved in trifluoracetic anhydride 2% in acetic anhydride (5 mL). The reaction mixture was stirred for 4 h at room temperature or 70° C if product was not soluble at room temperature and then evaporated under reduced pressure. The crude product was directly used in the next step. In the case of imino diaceticacids 9a and 18a, a stirred solution of diacid (5 mmol) in THF (10 mL) was added DCC (6 mmol). The resulting mixture was stirred at room temperature for 5 h and evaporated. 2) anhydride opening by amines: The crude anhydride (1 mmol) was solubilised in anhydrous DMF (5 mL). Then corresponding amine (1 mmol) (free base) and DIEA (4 mmol) was added. The mixture is stirred at room temperature under argon overnight. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC. Trityle protections were removed using TFA/DCM/TIS (5/90/5v/v) mixtures and final compounds were purified by preparative HPLC if needed. | |
With N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; | 1 A mixture of methylimino diacetic acid (1) (1 eq), chloro-N,N,N′N,NrTetramethylformamidinium hexafluorophosphate (TCFH) (1 eq), and N,N-diisopropylethylamine (DIEA) (2 eq) in dry DMF was stirred for one hour at room temperature. A solution of glycine tert-butyl ester (2) (1 eq) and DIEA (1 eq) in DMF was added to the mixture and stirred overnight to obtain product (3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In ethylene glycol at 190℃; for 4h; | |
84% | In ethylene glycol at 180℃; | |
77.3% | In ethylene glycol at 180℃; for 8h; |
53.5% | at 180℃; | |
Yield given. Multistep reaction; | ||
6.88 g (87.0%) | In water; ethylene glycol | 1 Preparation of N,N-bis(1H-benzimidazol-2-ylmethyl)-N-methylamine (L-1) EXAMPLE 1 Preparation of N,N-bis(1H-benzimidazol-2-ylmethyl)-N-methylamine (L-1) A mixture of 4.00 g (27.2 mmol) N-methyliminodiacetic acid and 5.99 g (54.4 mmol) o-phenylene diamine in 30 ml ethylene glycol was stirred at 190° C. for 4 hours. The water produced during was distilled off continuously. At the end of the reaction, the reaction mixture was allowed to cool down to room temperature and then poured in 150 ml water. The obtained slurry was triturated for 30 min, filtered, washed with water (3*30 ml) and dried at 60° C. under reduced pressure for 48 hours. Yield 6.88 g (87.0%). 1H NMR (250 MHz, DMSO-d6), δ 2.25 (s, 3H), 3.90 (s, 4H), 7.15 (m, 4H), 7.47-4.58 (m, 4H), 12.33 (br. s, 2E). Microanalysis, %: Calculated for C17H17N5: C 70.10, H 5.84, N 24.05. Found: C 70.22, H 6.05, N 23.76. +CI MS (m/z): [292]. (+CI-MS is Positive Chemical Ionisation Mass Spectroscopy). |
With ethylene glycol at 190℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In N,N-dimethyl-formamide; toluene equimolar amts. of educts refluxed for 1 h; solvent distd. (vac.), residue recrystd. (MeOH); elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 2,6-dimethylpyridine In dimethyl sulfoxide treatment of boron compd. with acetic acid deriv. in presence of lutidine in DMSO at 0 with warming to 23°C; | |
60% | With 2,6-dimethylpyridine In dimethyl sulfoxide at 23℃; for 48h; | |
60% | With 2,6-dimethylpyridine In dimethyl sulfoxide at 0 - 23℃; for 48.25h; | 11 Example 11; Synthesis of Protected Haloalkenylboronic Acid 54a; (E)-(2-bromoethenyl)dibromoborane (59) was synthesized according to a literature procedure (Hyuga, S., 1987). A subsequent reaction with 59 was conducted in a subdued light environment in an oven-dried 500 mL three-neck round bottom flask equipped with a magnetic stir bar. To a stirred mixture of N-methyliminodiacetic acid (MIDA, 1) (16.93 g, 113.9 mmol, 1.50 eq.) and 2,6-lutidine (17.69 mL, 151.86 mmol, 2.0 eq.) in DMSO (250 mL) at 0° C. under nitrogen was added freshly distilled 59 (21.00 g, 75.93 mmol) dropwise via syringe over 15 min. The reaction mixture was allowed to warm to 23° C. and then stirred at 23° C. for 48 h. The resulting yellow mixture was treated with water (300 mL) and extracted with THF:diethyl ether 1:1 (3×500 mL). The combined organic phases were washed with brine (3×350 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to provide a light yellow solid. The crude product was purified by flash chromatography on silica gel (EtOAc:petroleum ether 1:1→EtOAc→EtOAc:MeCN 9:1) to give 54a as a colorless crystalline solid (11.98 g, 45.75 mmol, 60%). Crystals suitable for X-ray crystallography analysis were grown by slow evaporation from ethyl acetate at 23° C. This material was stored under air at 23° C. for one year and six months without decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Vinyl-MIDA-Boronate (306); To a dry 6 mL vial fitted with a septum cap, equipped with a stir bar, and placed under Ar atmosphere was added BBr3 in CH2Cl2 (1.3 mL, 1.0 M, 1.3 mmol). To the stirred solution was added vinyltrimethylsilane (140 muL, 0.983 mmol). The solution was stirred at room temperature for 13 h. Separately, a dry 25 mL round bottom flask equipped with a stir bar, fitted with a rubber septum, and placed under Ar atm. was charged with sodium N-methyliminodiacetate (478 mg, 2.50 mmol) and DMSO (4 mL). To this stirred suspension was added dropwise by syringe the crude vinylboron dibromide solution. The mixture was stirred for 5 min. The mixture was concentrated in vacuo. The residue was adsorbed onto Florisil gel from an acetone suspension. The resulting powder was dry-loaded onto a silica gel column slurry packed in Et2O. The column was flushed with Et2O (app. 200 mL), then was eluted with Et2O:MeCN (3:1) to afford 306 as a colorless solid, 88 mg (48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: bromobenzene; Triisopropyl borate With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 0.75h; Stage #2: N-methyliminodiacetic acid In tetrahydrofuran; dimethyl sulfoxide for 3h; Heating / reflux; | 20 Example 20; Preparation of Protected Organoboronic Acids Without the Formation of the Corresponding Free Boronic Acid; Phenyl-MIDA-Boronate (304); To a dry 100 mL Schlenk flask equipped with a stir bar, fitted with a rubber septum, and placed under Ar atmosphere, was added THF (25 mL), bromoboenzene (2.0 mL, 19 mmol) and triisopropyl borate (5.3 mL, 23 mmol). The stirred solution was cooled to -78° C. To the solution was added n-BuLi (9.1 mL, 2.5 M, 23 mmol). The pale orange solution was stirred for 15 min. The solution was allowed to warm to room temperature with stirring for 30 min. To the solution was added DMSO (15 mL) and N-methyliminodiacetic acid (8.39 g, 57.1 mmol). The flask was fitted with a distillation apparatus. The mixture was brought to reflux, and as solvent was distilled the distillation pot was periodically charged with toluene to maintain a constant volume. The crude reaction mixture was concentrated in vacuo to afford an off-white solid. To the flask was added acetone (200 mL). The resulting suspension was filtered through a thin pad of celite. The filtrate was concentrated in vacuo. The resulting residue was adsorbed onto Florisil gel. This powder was dry-loaded onto a silica gel column slurry packed in Et2O. The column was flushed with Et2O (approximately 400 mL), then was eluted with Et2O:MeCN (5:1) to afford 304 as a colorless solid, 3.592 g (81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 80℃;Molecular sieve; Inert atmosphere; | 0.4 mmol of 4-formylphenylboronic acid, 0.5 mmol of N-methyliminodiacetic acid, 4Å molecular sieve (40 mg)After dissolving in N, N-dimethylformamide,Under an argon atmosphereStir at 130 C.The amount of 4-formyl phenyl bromic acid consumed was checked to complete the reaction, and the mixture was cooled to 80 C to produce a compound represented by formula (32). | |
In N,N-dimethyl-formamide; at 130℃;Molecular sieve; Inert atmosphere; | Formyl phenylboronic acid (0.5 mmol), N-methyliminodiacetic acid (1.5 mmol) and 4A molycularis (200 mg) were dissolved in 4 mL of N, N-dimethylformamide (DMF).The reaction mixture was stirred in an argon atmosphereThe reaction mixture was heated to 130 C and stirred.Respectively. After completion of the reaction, the reaction mixture was cooled to room temperature.[0228](I). Without filtration or separation, (a) into the cooled mixtureA mixture of 1,2-phenylenediamine (1, 0.55 mmol; 1.1 eq) and a catalytic amount of KI (0.1 mmol, 0.2 eq)And the inner wall was washed with 1 mL of DMFAnd the mixture was stirred in an atmosphere exposed to air at 80 C.When the mixture prepared in (A) was exhausted, the reaction was terminated and the reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The mixtureAnd purified by solid column chromatography to prepare a benzimidazole derivative substituted with a boronic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In dimethyl sulfoxide; benzene for 8h; Reflux; | |
78% | In dimethyl sulfoxide; toluene for 8h; Inert atmosphere; Reflux; | 1 To form protected organoboronic acid 2c, the general procedure was followed using thiophene-2-boronic acid (4.871 g, 38.06 mmol, Sigma-Aldrich), N-methyl iminodiacetic acid (5.884 g, 39.99 mmol), benzene (180 mL) and DMSO (20 mL). The mixture was refluxed for 8 h. The product was eluted with Et2θ -> Et2θ:MeCN 2:1. The solid thus obtained was dissolved in a minimum of acetone, to which Et2θ was slowly added to promote crystallization. Filtration of the mixture afforded 2c as a colorless crystalline solid (7.13 g, 78%). TLC (EtOAc) Rf = 0.34, visualized by UV (254 and 366 nm) and KMnO4 stain. 1H-NMR (500 MHz, CD3CN) δ 7.62 (dd, / = 5.0, 1.0 Hz, 1 H), 7.28 (dd, / = 3.5, 1.0 Hz, 1 H), 7.19 (dd, / = 5.0, 3.5 Hz, 1 H), 4.07 (d, / = 1 7 Hz, 2H), 3.90 (d, / = 18 Hz, 2H), 2.58 (s, 3H). 13C-NMR (125 MHz, CD3CN) δ 169.1, 134.2, 130.7, 129.5, 62.4, 48.3. 11 B-NMR (96 MHz, CD3CN) δ 11.2. HRMS (El +) Calculated for C9H10BNO4S (M) + : 239.0424, Found: 239.0432. IR (thin film, cm-1) 3007, 2954, 1773, 1704, 1514, 1457, 1421 , 1337, 1285, 1226, 1 172, 1029, 979, 894, 860, 814, 713. |
In dimethyl sulfoxide; toluene Dean-Stark; Reflux; Inert atmosphere; Sealed tube; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Stage #1: N-tert-butyloxycarbonyl-pyrrole With n-butyllithium; Triisopropyl borate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃; Stage #2: N-methyliminodiacetic acid In dimethyl sulfoxide at 75℃; for 2h; | |
29% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃; for 3.16667h; Inert atmosphere; Stage #2: N-tert-butyloxycarbonyl-pyrrole In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #3: N-methyliminodiacetic acid Inert atmosphere; | 3 To a 50 mL Schlenk flask equipped with a stir bar was added THF (15 mL) and diisopropylamine (920 microliters). The solution was cooled to -78 0C and then to the stirred solution was added dropwise n-BuLi (2.5 M in hexanes, 2.75 mL). The solution was maintained at -78 0C for 10 min, and then was allowed to warm to room temperature with stirring for 3 h. The solution was cooled to -78 0C, and to the stirred solution was added dropwise via cannula N-te/t-butoxycarbonylpyrrole (1.016 g, 6.074 mmol) as a solution in THF (15 mL + 10 mL washing). The solution was stirred for 30 min. To the yellow solution was added dropwise triisopropylborate (1.40 mL, 6.07 mmol). The solution was stirred for 10 min at -78 0C and then was allow to warm to room temperature with stirring overnight (1 1 h). To the near-black solution was added DMSO (15 mL). The THF was then removed in vacuo and the resulting DMSO solution was transferred to a 50 mL pressure-equalizing addition funnel. The funnel was fitted onto a 100 mL 3-neck round-bottom flask charged with N-methyliminodiacetic acid (1.407 g, 9.563 mmol) and DMSO (20 mL). To a second neck was fitted a short-path distillation apparatus connected to vacuum. The third neck of the flask was sealed with a septum. The system was placed under vacuum (1 Torr) and the mixture was heated to 75 0C upon which the DMSO began to distill. The DMSO solution of lithium triisopropyl 2-(N-te/t-butoxycarbonyl)pyrrole borate was added to the distilling mixture dropwise over 1 h. The mixture was further distilled to near dryness (1 h). The resulting residue was suspended in acetone and concentrated in vacuo onto Celite (10 g). The resulting powder was lyophilized for one day to remove additional DMSO and then was subjected to flash chromatography on silica gel (Et2O:MeCN, 100:0 -» 80:20) to afford 2e as an off-white crystalline solid (565 mg, 29%). This method is depicted in the scheme below.[00129] TLC (EtOAc) Rf = 0.35, stained with KMnO4. 1H-NMR (500 MHz,CD3CN) δ 7.38 (dd, / = 3.0, 1 .5 Hz, 1 H), 6.61 (dd, / = 3.0, 1.5 Hz, 1 H), 6.20 (t, / = 3.0 Hz, 1 H), 4.09 (d, / = 17 Hz, 2H), 4.05 (d, 17 Hz, 2H), 2.79 (s, 3H), 1.54 (s, 9H). 13C-NMR (125 MHz, CD3CN) δ 169.9, 151.2, 126.2, 124.9, 1 12.1 , 84.9, 65.9, 49.9, 28.0. 11 B-NMR (96 MHz, CD3CN) δ 1 1.1. HRMS (El + ) Calculated for C14H20BN2O6 (M + H) + : 323.1414, Found: 323.1414. IR (KBr, cm -1) 3174, 31 18, 3012, 2982, 2941 , 1743, 1457, 1337, 1304, 1296, 1253, 1235, 1 146, 1027, 1008, 815, 747. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In dimethyl sulfoxide; toluene for 2h; Reflux; | |
74% | In dimethyl sulfoxide; toluene for 2h; Inert atmosphere; Reflux; | 1 To form protected organoboronic acid 2h (Uno, 2009), the general procedure was followed using cyclopropyl boronic acid (5.139 g, 59.82 mmol, purchased from Oakwood Products), N-methyliminodiacetic acid (10.56 g, 71.79 mmol), DMSO (20 mL) and toluene (20 mL). The mixture was refluxed for 2 h. The mixture was cooled to room temperature and then was concentrated in vacuo (1 Torr, 100 0C). Although the product is stable to chromatography, for convenience the purification step was modified to employ crystallization. The residue oil was suspended in EtOAc (500 mL) and was transferred to a 2 L separatory funnel. The mixture was washed with water (250 mL). The aqueous phase was extracted with EtOAc (3 x 250 mL). The combined organics were washed with brine (50 mL) and then were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product was dissolved in acetone (approximately 100 mL), and then was diluted slowly over 1 h with Et2O (1.5 L) to promote crystallization of the product. The mixture was filtered to isolate 2h as a colorless, crystalline solid (8.775 g, 74%). TLC (EtOAc) Rf = 0.21 , stained with KMnO4. 1H-NMR (500 MHz, CD3CN) δ 3.92 (d, / = 17 Hz, 2H), 3.80 (d, / = 1 7 Hz, 2H), 2.98 (s, 3H), 0.46 (dq, / = 9.5, 3.0 Hz, 2H), 0.12 (m, 2H), -0.33 (m, 1 H). 13C-NMR (125 MHz, acetone-d6) δ 169.0, 62.7, 46.8, 1.2. 11B-NMR (96 MHz, CD3CN) δ 13.2. HRMS (FAB + ) Calculated for C8H13BNO4 (M + H) + : 198.0938, Found: 198.0937. IR (thin film, cm -1) 2998, 1744, 1457, 1358, 1337, 2197, 1246, 1 129, 1048, 985, 956, 892, 880, 845, 704. |
Yield | Reaction Conditions | Operation in experiment |
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93% | In dimethyl sulfoxide; benzene; for 3h;Inert atmosphere; Reflux; | To form protected organoboronic acid 2j, the general procedure was followed using <strong>[191162-40-0]N-methylindole-2-boronic acid</strong> (3.00 g, 17.1 mmol), N-methyliminodiacetic acid (2.77 g, 18.9 mmol), benzene (60 mL) and DMSO (30 mL). The mixture was refluxed for 3 h. The product was eluted with Et2theta:MeCN 2:1 to afford the boronate ester 2j as a colorless crystalline solid (4.55 g, 93%). TLC (EtOAc) Rf = 0.39, visualized by UV (254 nm) and KMnO4. 1H-NMR (500 MHz, CD3CN) delta 7.57 (app dt, / = 8.0, 1.0 Hz, 1 H), 7.39 (dd, / = 8.0, 1.0 Hz, 1 H), 7.20 (ddd, / = 8.0, 7.0, 1.0 Hz, 1 H), 7.04 (ddd, / = 8.0, 7.0, 1.0 Hz, 1 H), 6.66 (d, / = 1.0 Hz, 1 H), 4.07 (d, / = 1 7 Hz, 2H), 3.92 (d, / = 1 7 Hz, 2H), 3.82 (s, 3H), 2.56 (s, 3H). 13C-NMR (125 MHz, CD3CN) delta 169.4, 141.3, 129.0, 122.9, 121.5, 120.0, 1 1 1.4, 1 10.6, 62.3, 47.8, 32.8. 11 B-NMR (96 MHz, CD3CN) delta 10.8. HRMS (EI +) Calculated for C14H15BN2O4 (M) + : 286.1 125, Found: 286.1 127. IR (thin film, cm -1) 3000, 2948, 1765, 1653, 1617, 1508, 1456, 1509, 1456, 1360, 1332, 1276, 1236, 1 161 , 1037, 998, 962, 897, 859. |
Yield | Reaction Conditions | Operation in experiment |
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54% | In tetrahydrofuran; dimethyl sulfoxide; toluene; at 95 - 115℃; | Example 4Preparation of Vinyl MIDA Boronate from Corresponding Grignard ReagentTo a dry 500 mL Schlenk flask equipped with a stir bar was added THF (100 mL) and B(OMe)3 (11.7 mL, 105 mmol). The solution was cooled via a -78 C. cold bath. To the solution was added via cannula over 5 min. vinylmagnesium bromide as a solution in THF (1.0 M, 100 mL, 100 mmol). The resulting mixture was stirred for 2 h, then the cold bath was removed and the mixture was allowed to warm to room temperature with stirring for 2 h. The beige mixture was transferred to a 250 mL pressure-equalizing addition funnel. A 3-neck 500 mL round bottom flask equipped with a stir bar was charged with DMSO (100 mL), N-methyliminodiacetic acid (29.5 g, 200 mmol) and toluene (50 mL). To the necks of the round bottom were fitted the addition funnel, a thermometer, and a std. distillation apparatus. The mixture was heated to an internal temperature of 115 C. upon which the THF mixture was added via the addition funnel at a rate to maintain an internal temperature between 95-110 C. During this time the THF is distilled away from the hot DMSO mixture. Upon completion of the addition and after the internal temperature had risen to 120 C. the distillation pot was allowed to cool to room temperature.The DMSO mixture was diluted with acetone (300 mL) and the resulting mixture was filtered through a pad of Celite. The collected solids were extracted with acetone (100 mL) and the combined filtrate was concentrated in vacuo to afford a DMSO solution. The DMSO solution was distilled to near dryness (1 Torr, 100 C.). The remaining solids were dissolved in acetone:water (100 mL:100 mL) and were transferred to a 1000 mL separatory funnel. The solution was diluted with brine (100 mL) and EtOAc (200 mL). The mixture was shaken and the phases were separated. The aq. phase was twice extracted with acetone:EtOAc (100 mL:200 mL). The combined organics were washed with brine (3×100 mL). The combined brine washes were back-extracted with EtOAc (100 mL). The combined organics were dried over MgSO4, filtered, then concentrated in vacuo to afford an off-white solid which was then recrystallized from acetone (100 mL) diluted with Et2O (2000 mL) to afford the product 7c as an off-white solid (9.95 g, 54%). |
Yield | Reaction Conditions | Operation in experiment |
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86% | In dimethyl sulfoxide; toluene; for 4.5h;Reflux; | Step 1: 2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione To a 50 mL round bottom flask equipped with a stir bar was added <strong>[957120-61-5]5-bromo-2-fluoro-3-methylphenylboronic acid</strong> (1.0 g, 4.3 mmol), N-methyliminodiacetic acid (0.76 g, 5.2 mmol), toluene (8 mL) and DMSO (2 mL). The flask was fitted with a Dean-Stark trap and the Dean-Stark trap was fitted with a reflux condenser. The mixture was heated to reflux with azeotropic removal of water for 4.5 h. The solution was concentrated in vacuo. The residue was absorbed on Celite in vacuo from an acetone suspension and the resulting powder was subjected to Isco flash chromatography eluted with 0 to 70% acetonitrile in ether to give 2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (1.26 g, 86%). |
Yield | Reaction Conditions | Operation in experiment |
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80% | With calcium hydride In dimethyl sulfoxide; toluene at 120℃; for 16h; Inert atmosphere; | 4.4.11. 3,5,7,3',4'-Penta-O-benzyl-catechin-4β-(2-ethoxyethyl)ether-8-(N-methyliminodiacetyl)-boronate ester (19) To a stirring solution of 18 (1.11 g, 1.27 mmol) and N-methyliminodiacetic acid (0.38 g, 2.58 mmol, 2 equiv) in toluene/DMSO (25 mL/2.5 mL) at room temperature, solid CaH2 (0.53 g, 12.6 mmol, 10 equiv) was added and the resulting mixture was stirred at room temperature for 5 min before being refluxed at 120 °C for 16 h. The mixture was cooled to room temperature and filtered over Celite. The filter cake was washed with CH2Cl2 (3×10 mL) and the combined organics were washed with brine (4×50 mL), then dried (Na2SO4), filtered and concentrated. The residue was purified by SiO2 chromatography (CH2Cl2, then CH2Cl2/Et2O 90:10) to provide a white, amorphous solid (1.01 g, 80%). 1H NMR (600 MHz, CDCl3) δ 7.51-7.26 (m, 20H), 7.20-7.19 (m, 4H), 7.00-6.93 (m, 4H), 6.17 (s, 1H, C6-H), 5.33 (d, 1H, J=10.8 Hz, C2-H), 5.19-4.98 (m, 8H, 4× Ph-O-CH2-Ph), 4.80 (br s, 1H, C4-H), 4.15 (dis m, 1H, C3-O-CH2-Ph), 4.07 (dis m, 1H, C4-O-CH2CH2-OEt), 3.99 (dis m, 1H, C3-O-CH2-Ph), 3.87 (dis m, 1H, C4-O-CH2CH2-OEt), 3.58 (dis m, 3H, C3-H and C4-O-CH2CH2-OEt), 3.5-3.30 (overlapping m, 6H, C4-O-CH2CH2-O-CH2CH3 and 2× B(MIDA)-CH2), 2.46 (s, 3H, B(MIDA)-N-CH3), 1.17 (t, 3H, C4-O-CH2CH2-O-CH2CH3). 13C NMR (125 MHz, CDCl3) δ 167.94 (B(MIDA)-carbonyl), 167.86 (B(MIDA)-carbonyl), 164.9, 159.7, 159.6, 148.7, 148.2, 137.6, 137.5, 137.2, 136.8, 136.5, 131.2, 130-126 (Benzyl Ar-H), 121.1, 114.4, 113.7, 104.5, 92.1 (C6), 75.4 (C3), 71.8 (C2), 71.1 (O-CH2-Ph), 71.0 (2× O-CH2-Ph), 70.9 (C4), 70.3 (O-CH2-Ph), 70.1 (O-CH2-Ph), 69.9 (C4-O-CH2CH2-O-CH2CH3), 66.0 (2× C4-O-CH2CH2-OEt), 63.0 (B(MIDA)-CH2), 62.6 (B(MIDA)-CH2). 46.9 (B(MIDA)-N-CH3), 15.1 (C4-OCH2CH2-OCH2CH3). 11B NMR (126 MHz, CD3CN) δ 12.7. HRMS (ESI): Calculated for C59H5811BNO12, [M+Na+], 1006.3944, found 1006.3950. FTIR (thin film): 3062, 3031, 2926, 2869, 1766, 1595, 1496, 1451, 1429, 1301, 1265, 1209, 1126, 1090, 1028, 838, 737, 698. |
Yield | Reaction Conditions | Operation in experiment |
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35% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 2 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
In dimethyl sulfoxide; toluene for 1.5h; Reflux; | 6 Reference Example 6 Synthesis of 4-hydroxyphenyl boronic acid N-methylimino diacetic acid ester A suspension of 4-hydroxyphenyl boronic acid (10.3 g) and N-methylimino diacetic acid (11.0 g) in dimethyl sulfoxide (37 mL)-toluene (333 mL) was heated to reflux for 1.5 hours. From the resultant reaction mixture, toluene was distilled off under reduced pressure and the reaction mixture was poured into water (400 mL), followed by stirring the resultant reaction mixture for 1.5 hours. From the reaction mixture, precipitates were filtered and the precipitates were washed with water, followed by drying the deposit under reduced pressure to obtain the subject compound (16.4 g) as a gray white solid. | |
16.4 g | In dimethyl sulfoxide; toluene for 1.5h; Reflux; | 2 Synthesis of 4-hydroxyphenyl boronic acid N-methylimino diacetic acid ester A suspension of 4-hydroxyphenyl boronic acid (10.3 g) and N-methylimino diacetic acid (11.0 g) in dimethylsulfoxide (37 mL)-toluene (333 mL) was heated and refluxed for 1.5 hours. From the resultant reaction mixture, toluene was distilled off under reduced pressure and the reaction mixture was poured into water (400 mL), followed by stirring the resultant reaction mixture for 1.5 hours. From the reaction mixture, precipitates were filtered and the precipitates were washed with water, followed by drying the precipitates under reduced pressure to obtain the subject compound (16.4 g) as a gray white solid. |
16.4 g | In dimethyl sulfoxide; toluene for 1.5h; Reflux; | Synthesis of 4-Hydroxyphenylboronic Acid N-Methyliminodiacetic Acid Ester Reference Example 1 Synthesis of 4-Hydroxyphenylboronic Acid N-Methyliminodiacetic Acid Ester A suspension of 4-hydroxyphenylboronic acid (10.3 g) and N-methyliminodiacetic acid (11.0 g) in dimethyl sulfoxide (37 mL)- toluene (333 mL) was heated and refluxed for 1.5 hours. From the resultant reaction mixture, toluene was removed by evaporation under reduced pressure and the reaction mixture was poured into water (400 mL). The resultant reaction mixture was stirred for 1.5 hours. The precipitate was filtered, washed with water, and then dried under reduced pressure to give the title compound (16.4 g) as a gray white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.84 g | In dimethyl sulfoxide; toluene; for 16h;Reflux; | 6.3 g (28.4 mmol) of Intermediate 5A and 4.2 g (28.4 mmol) 2,2'-(methylimino)diacetic acid were dissolved in a mixture of 45 ml DMSO and 400 ml toluene and refluxed for 16 h using a Dean-Stark trap. After evaporation, the residue was taken up in ethyl acetate and washed three times with water and once with brine. The organic phase was dried over magnesium sulfate and evaporated to a volume of about 200 ml. A white solid precipitated which was filtered, washed with ethyl acetate and dried in vacuo to give a first crop (5.52 g) of the title compound. A second crop (3.32 g) was obtained after evaporation of the mother liquor and flash-chromatography over a layer of silica gel using cyclohexane/0-100% ethyl acetate as the eluent. Yield: 8.84 g (overall purity 92.5% by LC-MS, 87% of th.) LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 334 (M+H)+ -NMR (400 MHz, DMSO-de): δ = 7.42 (s, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 4.40 (d, 2H), 4.17 (d, 2H), 3.92 (s, 3H), 2.63 (s, 3H), 2.42 (s, 3H) ppm. |
In dimethyl sulfoxide; toluene; for 16h;Reflux; | 2-(7-Methoxy-5-methyl-1-benzothiophen-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 6.3 g (28.4 mmol) of Intermediate 5A and 4.2 g (28.4 mmol) 2,2'-(methylimino)diacetic acid were dissolved in a mixture of 45 ml DMSO and 400 ml toluene and refluxed for 16 h using a Dean-Stark trap. After evaporation, the residue was taken up in ethyl acetate and washed three times with water and once with brine. The organic phase was dried over magnesium sulfate and evaporated to a volume of about 200 ml. A white solid precipitated which was filtered, washed with ethyl acetate and dried in vacuo to give a first crop (5.52 g) of the title compound. A second crop (3.32 g) was obtained after evaporation of the mother liquor and flash-chromatography over a layer of silica gel using cyclohexane/0-100% ethyl acetate as the eluent. Yield: 8.84 g (overall purity 92.5% by LC-MS, 87% of th.) LC-MS (method 2): Rt=0.93 min; MS (ESIpos): m/z=334 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): δ=7.42 (s, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 4.40 (d, 2H), 4.17 (d, 2H), 3.92 (s, 3H), 2.63 (s, 3H), 2.42 (s, 3H) ppm. | |
In dimethyl sulfoxide; toluene; for 16h;Dean-Stark; Reflux; | 6.3 g (28.4 mmol) of Intermediate 5A and 4.2 g (28.4 mmol) 2,2'-(methylimino)diacetic acid were dissolved in a mixture of 45 ml DMSO and 400 ml toluene and refluxed for 16 h using a Dean- Stark trap. After evaporation, the residue was taken up in ethyl acetate and washed three times with water and once with brine. The organic phase was dried over magnesium sulfate and evaporated to a volume of about 200 ml. A white solid precipitated which was filtered, washed with ethyl acetate and dried in vacuo to give a first crop (5.52 g) of the title compound. A second crop (3.32 g) was obtained after evaporation of the mother liquor and flash-chromatography over a layer of silica gel using cyclohexane/0-100 ethyl acetate as the eluent. Yield: 8.84 g (overall purity 92.5% by LC-MS, 87% of th.) LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 334 (M+H)+ -NMR (400 MHz, DMSO-d6): δ = 7.42 (s, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 4.40 (d, 2H), 4.17 (d, 2H), 3.92 (s, 3H), 2.63 (s, 3H), 2.42 (s, 3H) ppm. |
8.84 g | In dimethyl sulfoxide; toluene; for 16h;Reflux; | 6.3 g (28.4 mmol) of Intermediate 5A and 4.2 g (28.4 mmol) 2,2'-(methylimino)diacetic acid were dissolved in a mixture of 45 ml DMSO and 400 ml toluene and refluxed for 16 h using a Dean-Stark trap. After evaporation, the residue was taken up in ethyl acetate and washed three times with water and once with brine. The organic phase was dried over magnesium sulfate and evaporated to a volume of about 200 ml. A white solid precipitated which was filtered, washed with ethyl acetate and dried in vacuo to give a first crop (5.52 g) of the title compound. A second crop (3.32 g) was obtained after evaporation of the mother liquor and flash-chromatography over a layer of silica gel using cyclohexane/0-100% ethyl acetate as the eluent. Yield: 8.84 g (overall purity 92.5% by LC-MS, 87% of th.) LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 334 (M+H)+ -NMR (400 MHz, DMSO-de): δ = 7.42 (s, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 4.40 (d, 2H), 4.17 (d, 2H), 3.92 (s, 3H), 2.63 (s, 3H), 2.42 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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55% | To a 3 L three-neck round bottom flask equipped with a stir bar were added B(OMe)3 (94 mL, 840 mmol) and THF (600 mL). The solution was cooled to 78 C. Vinylmagnesium bromide (1.0 M in THF, 800 mL, 800 mmol) was added dropwise via cannula over 2 h 45 min. The resulting solution was stirred at 78 C for 15 min, followed by stirring at 23 C for 2 h 30 min. In a separate 2 L three neckround bottom flask equipped with a stir bar, internal thermometer, and distillation apparatus were added dry MIDA (235.0 g, 1.6 mol) and DMSO (600 mL). The solution was heated with an oil bath to an internal temperature of 110-115 C. The borate suspension was added dropwise to the hot MIDA solution via a Teflon cannula dropwise over 2 h 10 min, keeping the internal temperature between 105 and 115 C. After full addition of the borate solution, the reaction solution was cooled to 23 C. The resulting solution was transferred to a separatory funnel containing H2O (1 L), brine (1 L), EtOAc (1.5 L), and acetone (1 L). The mixture was shaken and the aqueous layer was removed and extracted with EtOAc/acetone (2:1, 2600 mL). The combined organic layers were washed with H2O (2500 mL). The combined water washes were back extracted with EtOAc/acetone (2:1, 2300 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was suspended in 300 mL acetone and 4 L Et2O was added to precipitate the product. The resulting solid was collected by vacuum filtration to yield vinyl MIDA boronate 1 as a white solid (81.2 g, 55%). Spectral data for 1 were consistent with those previously reported from our laboratories.13 |
Yield | Reaction Conditions | Operation in experiment |
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96% | In N,N-dimethyl-formamide at 120℃; for 3h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | for 20h; Dean-Stark; Reflux; | |
72% | In N,N-dimethyl-formamide at 130℃; for 0.166667h; Microwave irradiation; | 18 3.3. General procedure for MIDA boronate formation with DMF (general method B) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, followed by methyliminodiacetic acid (MIDA) (1 mmol) and dry DMF (1 mL) was added to the vial. The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with max power set to 300 W, max pressure 300 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 10 min. After cooling, the DMF was removed under reduced pressure giving crude yellow oil. The latter was triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with cold water (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) then air dried giving pure product as a white precipitate. |
Yield | Reaction Conditions | Operation in experiment |
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97% | In N,N-dimethyl-formamide at 130℃; for 0.166667h; Microwave irradiation; | 19 3.3. General procedure for MIDA boronate formation with DMF (general method B) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, followed by methyliminodiacetic acid (MIDA) (1 mmol) and dry DMF (1 mL) was added to the vial. The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with max power set to 300 W, max pressure 300 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 10 min. After cooling, the DMF was removed under reduced pressure giving crude yellow oil. The latter was triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with cold water (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) then air dried giving pure product as a white precipitate. |
Yield | Reaction Conditions | Operation in experiment |
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82% | at 130℃; under 12929.0 Torr; for 0.0833333h;Microwave irradiation; | General procedure: The boronic acid (1 mmol) was added to a 10 mL microwave vial equipped with a magnetic stirrer, and then PEG 300 (1 mL) was added followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction was heated using the dynamic heating method, with max power set to 40 W, max pressure 250 psi, max temperature 130 C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 C for 5 min. After cooling, the mixture was added to water (9 mL). This mixture was stirred forming a white precipitate, then cooled in an ice bath allowing flocculation, then collected by filtration and washed with cold water (5 mL). The precipitate was allowed to dried in an oven set to 100 C, giving pure product as a white precipitate (if not otherwise quoted). Notes: The 5 mmol scale reaction was performed using a 35 mL microwave vial and the 10 mmol scale was carried out usinga 100 mL round bottomed flask with a small air condenser attached with the open vessel attenuator installed. The heating parameters were kept the same but the hold time was changed to 7.5 min for the 5 mmol scale and 10 min for the 10 mmol scale reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In N,N-dimethyl-formamide at 130℃; for 0.166667h; Microwave irradiation; | 21 3.3. General procedure for MIDA boronate formation with DMF (general method B) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, followed by methyliminodiacetic acid (MIDA) (1 mmol) and dry DMF (1 mL) was added to the vial. The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with max power set to 300 W, max pressure 300 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 10 min. After cooling, the DMF was removed under reduced pressure giving crude yellow oil. The latter was triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with cold water (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) then air dried giving pure product as a white precipitate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In N,N-dimethyl-formamide at 130℃; for 0.166667h; Microwave irradiation; | 23 3.3. General procedure for MIDA boronate formation with DMF (general method B) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, followed by methyliminodiacetic acid (MIDA) (1 mmol) and dry DMF (1 mL) was added to the vial. The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with max power set to 300 W, max pressure 300 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 10 min. After cooling, the DMF was removed under reduced pressure giving crude yellow oil. The latter was triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with cold water (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) then air dried giving pure product as a white precipitate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | In N,N-dimethyl-formamide; at 130℃; under 15514.9 Torr; for 0.166667h;Microwave irradiation; | General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, followed by methyliminodiacetic acid (MIDA) (1 mmol) and dry DMF (1 mL) was added to the vial. The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with max power set to 300 W, max pressure 300 psi, max temperature 130 C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 C for 10 min. After cooling, the DMF was removed under reduced pressure giving crude yellow oil. The latter was triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with cold water (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) then air dried giving pure product as a white precipitate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 1 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 3 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | at 130℃; under 12929.0 Torr; for 0.0833333h;Microwave irradiation; | General procedure: The boronic acid (1 mmol) was added to a 10 mL microwave vial equipped with a magnetic stirrer, and then PEG 300 (1 mL) was added followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction was heated using the dynamic heating method, with max power set to 40 W, max pressure 250 psi, max temperature 130 C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 C for 5 min. After cooling, the mixture was added to water (9 mL). This mixture was stirred forming a white precipitate, then cooled in an ice bath allowing flocculation, then collected by filtration and washed with cold water (5 mL). The precipitate was allowed to dried in an oven set to 100 C, giving pure product as a white precipitate (if not otherwise quoted). Notes: The 5 mmol scale reaction was performed using a 35 mL microwave vial and the 10 mmol scale was carried out usinga 100 mL round bottomed flask with a small air condenser attached with the open vessel attenuator installed. The heating parameters were kept the same but the hold time was changed to 7.5 min for the 5 mmol scale and 10 min for the 10 mmol scale reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 5 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 6 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In acetonitrile; at 130℃; under 12929.0 Torr; for 0.0833333h;Microwave irradiation; | General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 8 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In acetonitrile; at 130℃; under 12929.0 Torr; for 0.0833333h;Microwave irradiation; | General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 10 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
In N,N-dimethyl-formamide at 90℃; for 18h; | 46 Intermediate 46b: 2-fluoro-4-(6-methyl-4,8-dioxo-1 ,3,6,2-dioxazaborocan-2-yl)benzaldehyde A solution of (3-fluoro-4-formylphenyl)boronic acid (67 mg, 0.40 mmol) and N-methyl iminodiacetic acid (65 mg, 0.44 mmol) in DMF (2 mL) was stirred at 90 °C for 18 h. The reaction mixture was cooled and filtered through a SPE carbonate cartridge followed by washing three times withacetonitrile. The filtrate and the wash solutions were concentrated under reduced pressure to give the title compound which was used without further purification. ESI-MS 558 [2M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 11 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 12 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In acetonitrile at 130℃; for 0.0833333h; Microwave irradiation; | 3.2. General procedure for MIDA boronate formation with acetonitrile (general method A) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, and then acetonitrile (1 mL) was added, followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with the maximum power set to 300W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the magnetic stirrer was retrieved and the acetonitrile was removed under reduced pressure giving a crude white powder. This crude material was first triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with coldwater (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) giving pure product as a white precipitate (if not otherwise quoted), which was air dried. Notes: The 3.5 mmol scale reaction was done using a 35 mL microwave vial, with the same heating profile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide at 120℃; Molecular sieve; Inert atmosphere; | |
55% | at 130℃; for 0.0833333h; Microwave irradiation; | 14 3.4. General procedure for MIDA boronate formation with PEG 300 (general method C) General procedure: The boronic acid (1 mmol) was added to a 10 mL microwave vial equipped with a magnetic stirrer, and then PEG 300 (1 mL) was added followed by methyliminodiacetic acid (MIDA) (147 mg, 1 mmol). The Teflon cap was added and the reaction was heated using the dynamic heating method, with max power set to 40 W, max pressure 250 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 5 min. After cooling, the mixture was added to water (9 mL). This mixture was stirred forming a white precipitate, then cooled in an ice bath allowing flocculation, then collected by filtration and washed with cold water (5 mL). The precipitate was allowed to dried in an oven set to 100 °C, giving pure product as a white precipitate (if not otherwise quoted). Notes: The 5 mmol scale reaction was performed using a 35 mL microwave vial and the 10 mmol scale was carried out usinga 100 mL round bottomed flask with a small air condenser attached with the open vessel attenuator installed. The heating parameters were kept the same but the hold time was changed to 7.5 min for the 5 mmol scale and 10 min for the 10 mmol scale reactions. |
In dimethyl sulfoxide at 80 - 90℃; for 1h; |
In dimethyl sulfoxide at 80 - 90℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | for 20h; Dean-Stark; Reflux; | |
62% | In N,N-dimethyl-formamide at 130℃; for 0.166667h; Microwave irradiation; | 16 3.3. General procedure for MIDA boronate formation with DMF (general method B) General procedure: The boronic acid (1 mmol) was added to a 10mL microwave vial equipped with a magnetic stirrer, followed by methyliminodiacetic acid (MIDA) (1 mmol) and dry DMF (1 mL) was added to the vial. The Teflon cap was added and the reaction mixture was heated using the dynamic heating method, with max power set to 300 W, max pressure 300 psi, max temperature 130 °C, high stirring throughout and power max turned off. This method was used to hold the reaction mixture at 130 °C for 10 min. After cooling, the DMF was removed under reduced pressure giving crude yellow oil. The latter was triturated via sonication with deionised water (5 mL), cooled in an ice bath and collected by filtration and washed with cold water (5 mL). This solid was then further triturated with diethyl ether (5 mL), cooled in an ice bath, collected by filtration and washed with diethyl ether (5 mL) then air dried giving pure product as a white precipitate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridinium p-toluenesulfonate; silica gel In acetonitrile at 80℃; for 12h; Inert atmosphere; Sealed tube; | II.a To a 40-mL sealed I-Chem vial under nitrogen was added racemic potassium trans- 2-methylcyclohexyltrifiuoro borate 6b (1.02 g, 5 mmol), N-methyliminodiacetic acid (MIDA) (2.20 g, 15 mmol), pyridinium /?-toluenesulfonate (126 mg, 0.5 mmol) and silica gel (900 mg) followed by acetonitrile (16.7 mL, 0.3 M for the borate). The reaction was sealed and allowed to stir at 80 °C for 12 hours. After cooling down, the mixture was passed through a pad of silica gel before concentration. The light brown solid mixture was then loaded onto a silica gel column and flushed with copious amount of Et20, the product was then eluted by straight EtOAc. Upon concentration, the product 7b was obtained as a crystalline white solid ( 1.17 g, 93 %) . 1H NMR (499 MHz, DMSO) δ 4.17 (d, J = 17.0, 1H), 4.10 (d, J = 17.0, 1H), 3.98 (d, J = 17.0, 1H), 3.93 (d, J = 17.0, 1H), 2.89 (s, 3H), 1.66-1.56 (m, 4H), 1.44 (m, 1H) 1.24 (m, 1H), 1.15 (m, 1H), 1.09-0.96 (m, 2H), 0.95 (d, J = 6.5, 3H), 0.47 (m, 1H). 13C NMR (126 MHz, DMSO) δ 169.2, 168.7, 62.3, 62.0, 45.3, 36.3, 32.2, 26.5, 26.1 , 25.3, 22.7. HRMS (ESI+) Calculated for Ci2H2iBN04: 254.1564 Found: 254.1554 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridinium p-toluenesulfonate; In acetonitrile; at 80℃; for 12h;Inert atmosphere; Sealed tube; | a. Synthesis of chiral racemic MIDA boronates and boronic acids (+/-)-1a To a 40-mL sealed I-Chem vial under nitrogen was added racemic 2-butyl boronic acid (+/-)-la (710 mg, 5 mmol), N-methyliminodiacetic acid (MIDA) (2.20 g, 15 mmol), pyridinium /?-toluenesulfonate (126 mg, 0.5 mmol) followed by acetonitrile (16.7 mL, 0.3 M for the borate). The reaction was sealed and allowed to stir at 80 C for 12 hours. After cooling down, the mixture was passed through a pad of silica gel before concentration. The light brown solid mixture was then loaded onto a silica gel column and flushed with copious amount of Et20, the product was then eluted with straight EtOAc. Upon concentration, the product was obtained as a crystalline white solid (949 mg, 89%). 1H NMR (500 MHz, DMSO) delta 4.18 (d, J = 17.0, 1H), 4.16 (d, J = 17.0, 1H), 3.98 (d, J = 17.0, 2H), 2.87 (s, 3H), 1.47 (m, 1H), 1.03 (m, 1H), 0.88 (t, J = 7.5, 3H), 0.81 (d, J = 7.0, 3H), 0.67 (s, 1H). 13C NMR (126 MHz, DMSO) delta 169.1, 169.0, 62.3, 62.1, 45.4, 24.5, 13.8, 12.7. HRMS (ESI+) Calculated for C9H17BNO4: 214.1251 Found: 214.1252 |
In dimethyl sulfoxide; toluene; for 2h;Inert atmosphere; Dean-Stark; Reflux; | To a 250-mL round-bottom flask with a stir bar was added (±)-1a (1.02 g, 10 mmol, 1.0 eq, obtained from Frontier Scientific), N-methyliminodiacetic acid (MIDA) (1.77 g, 12 mmol, 1.2 eq), DMSO (10 mL, 1 Molar), and toluene (90 mL, 0.11 Molar). The mixture was fitted with a Dean Stark trap, on top of which was fitted a reflux condenser. The mixture was heated to reflux and water was collected in the trap for 2 hours, at which point complete conversion of the boronic acid was confirmed by TLC (100% EtOAc, KMnO4). The toluene was then removed by rotary evaporation. 75 mL of H2O was added, and the mixture was extracted with EtOAc (5×75 mL). The combined organic phase was washed with H2O (75 mL×5). The organic phase was then dried over Na2SO4 and concentrated under vacuum to give (±)-6a as a white solid (1.49 g, 70%), which was used without purification. This material was stable in a capped vial under air on a bench top for at least 4 months (see below). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridinium p-toluenesulfonate; silica gel In acetonitrile at 80℃; for 12h; Inert atmosphere; | (16) (a) Enabling fresh preparation of these boronic acids in excellent purity, we developed a novel method for direct transformation of trifluoroborate salts into the corresponding MIDA boronates, which in turn can be very efficiently hydrolyzed into the readily isolable corresponding boronic acids just prior to use in a reaction. Specifically, racemic If and l were prepared via direct transformation of commercially available trifluoroborate salts 6a and 6b into the corresponding MIDA boronates 7a and 7b. These air- and chromatographically stable crystalline solids were then readily hydrolyzed to the corresponding boronic acids If and l prior to the cross-coupling reactions reported in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In dimethyl sulfoxide; toluene for 4h; Reflux; | 10132] A slurry of (4-(4-fluorophenethoxy)phenyl)boronic acid (122 g, 469 mmol) and 2,2’-(methylazanediyl)diacetic acid (76 g, 516 mmol) in anhydrous toluene (500 mE) and DMSO (200 mE) was refluxed for 4 h. Then, cooled, diluted with EtOAc (500 mE), washed with water (5x200 mE), brine (2x 100 mE), dried (MgSO4), filtered and concentrated to give light orange foam which was purified by flash chromatography using 5-40% acetone/CH2C12 (5% increment per 2-lit) to afford 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1 ,3,6,2- dioxazaborocane-4,8-dione (131.38 g, 354 mmol, 75% yield) as white solid. ‘H NMR (500 MHz, CDC13) ö 7.43 (d, J=8.4 Hz, 2H), 7.28-7.24 (m, 2H), 7.04-6.99 (m, 2H), 6.92 (d, J=8.5 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H), 4.00 (d, J=16.6 Hz, 2H), 3.76 (d, J=16.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.54 (s, 3H). ECMS (M+H)=372.3. |
75% | In dimethyl sulfoxide; toluene for 4h; Reflux; | 2-(4-(4-Fluorophenethoxy)phenyl)-6-methyl-1, 3,6, 2-dioxazaborocane-4, 8-cl/one: A slurry of (4-(4-fluorophenethoxy)phenyl)boronic acid (122 g, 469 mmol) and 2,2’-(methylazanediyl)diacetic acid (76 g, 516 mmol) in anhydrous toluene (500 mL) and DMSO (200 mL) was refluxed for 4 h. Then, cooled, diluted with EtOAc (500 mL), washed with water (5 x 200 mL), brine (2 x 100 mL), dried (MgSO4), filtered and concentrated to give light orange foam which was purified by flash chromatography using 5-40% acetone/CH2C12 (5% increment per 2-lit) to afford 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl- 1,3 ,6,2-di oxazaborocane-4, 8-dione (131.38 g, 354mmol, 75 % yield) as white solid. ‘H NIVIR (500MHz, CDC13) ö 7.43 (d, J=8.4 Hz, 2H),7.28 - 7.24 (m, 2H), 7.04 - 6.99 (m, 2H), 6.92 (d, J=8.5 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H),4.00 (d, J16.6 Hz, 2H), 3.76 (d, J16.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.54 (s, 3H).LCMS (M+H) = 372.3. |
75% | In dimethyl sulfoxide; toluene for 4h; Reflux; | 2-(4-(4-Fluorophenethoxy)phenyl)-6-methyl-i, 3,6, 2-dioxazaborocane-4, 8-cl/one: A slurry of (4-(4-fluorophenethoxy)phenyl)boronic acid (122 g, 469 mmol) and 2,2’-(methylazanediyl)diacetic acid (76 g, 516 mmol) in anhydrous toluene (500 mL) and DMSO (200 mL) was refluxed for 4 h. Then, cooled, diluted with EtOAc (500 mL), washed with water (5 x 200 mL), brine (2 x 100 mL), dried (MgSO4), filtered and concentrated to give light orange foam which was purified by flash chromatography using 5-40% acetone/CH2C12 (5% increment per 2-lit) to afford 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl- 1,3 ,6,2-di oxazaborocane-4, 8-dione (131.38 g, 354mmol, 75 % yield) as white solid. ‘H NIVIR (500MHz, CDC13) ö 7.43 (d, J=8.4 Hz, 2H),7.28 - 7.24 (m, 2H), 7.04 - 6.99 (m, 2H), 6.92 (d, J=8.5 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H),4.00 (d, J16.6 Hz, 2H), 3.76 (d, J16.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.54 (s, 3H).LCMS (M+H) = 372.3. |
75% | In dimethyl sulfoxide; toluene for 4h; Reflux; | 2-(4-(4-Fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione A slurry of (4-(4-fluorophenethoxy)phenyl)boronic acid (122 g, 469 mmol) and 2,2'-(methylazanediyl)diacetic acid (76 g, 516 mmol) in anhydrous toluene (500 mL) and DMSO (200 mL) was refluxed for 4 h. Then, cooled, diluted with EtOAc (500 mL), washed with water (5 x 200 mL), brine (2 x 100 mL), dried (MgS04), filtered and concentrated to give light orange foam which was purified by flash chromatography using 5-40% acetone/CH2Cl2 (5% increment per 2-lit) to afford 2-(4-(4- fluorophenethoxy)phenyl)-6-methyl-l,3,6,2-dioxazaborocane-4,8-dione (131.38 g, 354 mmol, 75 % yield) as white solid. 1H NMR (500MHz, CDC13) δ 7.43 (d, J=8.4 Hz, 2H), 7.28 - 7.24 (m, 2H), 7.04 - 6.99 (m, 2H), 6.92 (d, J=8.5 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H), 4.00 (d, J=16.6 Hz, 2H), 3.76 (d, J=16.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.54 (s, 3H). LCMS (M+H) = 372.3. |
75% | In dimethyl sulfoxide; toluene for 4h; Reflux; | 2-(4-(4-Fluorophenethoxy)phenyl)-6-methyl-], 3,6, 2-dioxazaborocane-4 , 8-dione: A slurry of (4-(4-fluorophenethoxy)phenyl)boronic acid (122 g, 469 mmol) and2,2’-(methylazanediyl)diacetic acid (76 g, 516 mmol) in anhydrous toluene (500 mL) and DMSO (200 mL) was refluxed for 4 h. Then, cooled, diluted with EtOAc (500 mL), washed with water (5 x 200 mL), brine (2 x 100 mL), dried (MgSO4), filtered and concentrated to give light orange foam which was purified by flash chromatography using 5-40% acetone/CH2C12 (5% increment per 2-lit) to afford 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl- 1,3 ,6,2-dioxazaborocane-4, 8-dione (131.38 g, 354mmol, 75 % yield) as white solid. ‘H NMR (500MHz, CDC13) ö 7.43 (d, J=8.4 Hz, 2H),7.28 - 7.24 (m, 2H), 7.04 - 6.99 (m, 2H), 6.92 (d, J=8.5 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H),4.00 (d, J16.6 Hz, 2H), 3.76 (d, J16.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.54 (s, 3H).LCMS (M+H) = 372.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
760 mg | In dimethyl sulfoxide; toluene; at 125℃; for 3h;Dean-Stark; | 2- (4-Fluoro-2-hydroxyphenyl)-6-methyl-1, 3,6, 2-dioxazaborocane-4, 8-dione:2,2?-(Methylazanediyl)diacetic acid (0.566 g, 3.85 mmol) and (4-fluoro-2- hydroxyphenyl)boronic acid (0.50 g, 3.2 mmol) were taken up in toluene (4.3 ml) and DMSO (2.2 ml) at rt. The reaction mixture was equipped with Dean-Stark trap andthe mixture was stirred at 125 °C for 3 h. The reaction was allowed to cool to rt and was then taken up in EtOAc and water. The organic layer was separated,concentrated, adsorbed onto Celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient and flushed with acetone at the end, TLCs were visualized with permanganate stain). The fractions containing the expected product were concentrated to give 760 mg of the title compound as a white solid. ?H NMR(500MHz, DMSO-d6) oe 10.09 (s, 1H), 7.38 (t, J8.0 Hz, 1H), 6.60 (td, J=8.6, 2.4 Hz,1H), 6.53 (dd, J=11.2, 2.4 Hz, 1H), 4.33 (d, J=17.0 Hz, 2H), 4.02 (d, J17.0 Hz, 2H),2.63 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: Triisopropyl borate; 1-bromo-4-hexyloxylbenzene With n-butyllithium In tetrahydrofuran at -78℃; for 2.5h; Stage #2: N-methyliminodiacetic acid In tetrahydrofuran; dimethylsulfoxide-d6 for 2h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 70℃; for 0.416667h; | General procedure: The solutions contained 1) VO(acac)2 (5.3 g, 20.0 mmol), H2IDA (2.66 g, 20.0 mmol) and dmbipy (3.68 g, 17.0 mmol) in water (100 mL) and 2) VO(acac)2 (5.3 g, 20.0 mmol), mH2IDA (2.94 g,20.0 mmol) and dmbipy (3.68 g, 17.0 mmol) in water (100 mL) were heated about 25 min at 70°C in a heating mantle. Then, after several days, dark green crystals of [VO(mIDA)(dmbipy)*]1.5H2O and the grey-green powder of [VO(IDA)(dmbipy)]*2H2O were obtained. The composition of the studied compounds was established on the basis of the elemental analysis of carbon, hydrogen and nitrogen (CARBO ERBA type CHNS e O 1108). Anal. Calcd for [VO(mIDA)(dmbipy)]*1.5H2O (percent): C, 42.20, H, 4.84, N, 9.23. Found:C, 42.54, H, 4.94, N, 9.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.4% | In ethyl acetate at 20℃; | 3 Example 3 According to Example 1A total of 10 g (22.5 mmol) of compound 1-6 was prepared,Ethyl acetate (100 ml) and N-methyliminodiacetic acid were added(Compound 3-1, 3.31 g, 22.5 mmol),Stirred at room temperature overnight,filter,Ethyl acetate wash,Dried to give 9.5 g of the desired product,Yield 89.4%. |
61% | In ethyl acetate at 20℃; | 3 Example 3: N-2,5-Dichlorobenzoyl-L-glycine-L-leucine boronic acid pinacol ester (20.0 g, 45.1 mM, 1.0 eq)Dissolve in ethyl acetate (450 mL) and N-methylimidic acid (6.64 g, 45.1 mM, 1.0 eq), stir overnight at room temperature, filter, wash with ethyl acetate, and dry to obtain the desired product 12.9 g, yield 61% . |
58% | In dimethyl sulfoxide; toluene at 60℃; | 3 N-2,5-dichlorobenzoyl-L-glycine-L-leucine boronic acid pinacol ester IV-1 (7.0 g, 15.8 mM, 1.0 eq) was dissolved in a mixed solvent of toluene and dimethylsulfoxide (85: 5) (50 mL) and N-methyliminodiacetic acid (2.32 g, 15.8 mM, 1.0 eq) at 60 ° C overnight, solid filtered and the resulting solid was subjected to beating and purification with ethyl acetate A large amount of reaction produced by the process impurities, ethyl acetate washing, drying the target product 4.3g, yield 58%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; | For the synthesis of organosilane template, double-acylamino intermediate N,N-bis(2-(dodecylamino)-2-oxoethyl)-methylamine was prepared first. 2.04 g (0.014 mol) 2,2-(methylimino)bisacetic acid, 5.65 g (0.03 mol) dodecylamine, 3.92 g(0.03 mol) 1-hydroxy-1,2,3-benzotriazole (HOBT), 5.56 g (0.03mol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and 4.23 mL (0.03 mol) triethylamine were mixed in 100 mL N,N-dimethylformamide. The mixture was stirred overnight at room temperature. After the reaction, 50 mL saturated sodium bicarbonate solution was added to the mixture, and white solid was separated out, then the white solid was filtrated and washed with DMF, ethyl acetate, and diethyl ether. After washing, the intermediate was purified by recrystallization twice with n-hexane, washed fully with n-hexane during vacuum filtration, and dried under high vacuum at 70 °C. The structure of the intermediate was confirmed by FTMS, 1H NMR,and 13C NMR spectra. Its spectral data are as follows. Yield: 75%. FTMS m/z for C29H59N3O2 ([M + H]+) found:482.5; calculated: 482.5. 1H NMR (400 MHz, CDCl3): δ 6.69(s, 2H, 2 x NH), 3.303.27 (m, 4H, 2 x NHCH2), 3.12 (s,4H, 2 x COCH2), 2.39 (s, 3H, NCH3), 1.601.45 (m, 4H,2 x NHCH2CH2), 1.401.15 (m, 36H, 2 x (CH2)9), 0.89(t, J = 6.8, 6H, 2 x CH3). 13C NMR (100 MHz, CDCl3): δ169.55 (2 x C=O), 61.53 (2 x NCH2), 43.96 (NCH3), 39.28(2 x NHCH2), 31.93 (2 x NHCH2CH2), [29.6622.71, doublelong carbon chains 2 x (CH2)9], 14.15 (2 x CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In dimethyl sulfoxide; toluene at 105℃; for 2h; | General Method B for BPin-BMIDA exchange General procedure: To a solution of pinacol ester (1 eq.) in a 2:1 mixture of acetone and water ([pinacol ester = 0.1 M typically) were added ammonium acetate (3.1 eq.) and sodium periodate (3.1 eq.). The suspension was stirred at 80°C (reflux) for 2h. The mixture was then cooled down to room temperature and treated with a 0.5 M aqueous thiosulfate solution. The mixture was extracted with EtOAc until complete extraction confirmed by TLC. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and concentrated to afford the corresponding boronic acid. The crude residue was resuspended in a 3:1 mixture of toluene and DMSO ([boronic acid] = 0.1 M typically) and N-methyliminiodiacetic acid (MIDA, 3 eq.) was added. The suspension was stirred at 105°C for 2h. The mixture was then cooled down to room temperature and treated with diluted brine (30% brine in water) and the mixture was extracted with EtOAc. The combined organic extracts were dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (MeCN/CH2Cl2) to afford pure MIDA alkenyl-2-boronates. |
54.1 mg | In dimethyl sulfoxide; toluene at 105℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: N-(tert-butyl)-5-isobutylthiophene-2-sulphonamide With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 2h; Inert atmosphere; Stage #2: With Triisopropyl borate In tetrahydrofuran at -78 - 0℃; for 2h; Inert atmosphere; Stage #3: N-methyliminodiacetic acid In dimethyl sulfoxide; toluene for 5h; Reflux; | (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid MIDA ester (3) A solution of N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (4.29 g, 14.4 mmol) dissolved in dry THF (120 mL) was cooled to -78 °C and flushed with nitrogen. BuLi (1.6 M, 27 mL 43 mmol) was added over about 10 minutes, keeping the reaction solution below 0 °C. The reaction vessel was transferred to a water-ice bath and stirred at about 0 °C under N2 for 2 h. The now dark orange reaction mixture was then cooled again to -78 °C. Triisopropyl borate (6.6 mL, 29 mmol) was added over 5 min and the reaction stirred at 0 °C for 2 h. The reaction mixture was quenched with 1M HCl (aq., 50 mL) and partially evaporated. The mixture was diluted with water (100 mL) and extracted with DCM (3x50 mL). The combined organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. To the residue was added methyliminodiacetic acid (MIDA, 3.18 g, 21.6 mmol), DMSO (20 mL) and toluene (150 mL) the mixture was carefully refluxed in an open high-necked flask (allowing water to escape) for 5 h. The cold reaction mixture was partitioned between 0.1 M HCl (aq., 75 mL) and EtOAc (75 mL). The organic layer was washed with 0.1 M HCl (aq., 2x75 mL), dried with Na2SO4 and filtered, after which the solvent was evaporated. The light brown residue isolated was dissolved in acetone (15 mL) and diethyl ether (15 mL) was added. Slow drop-wise addition of hexanes (220 mL) produced a white precipitate overnight. The precipitate was filtered and washed with hexanes (ca 20 mL) and dried under vacuum overnight to give 5.119 g (83%) of (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid MIDA ester as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 6.87 (br s, 1H), 5.21 (s, 1H), 4.01 (br s, 4H), 2.82 (s, 3H), 2.66 (dd, J = 7.1, 0.8Hz, 2H), 1.89 (app. hept, J = 6.8 Hz, 1H), 1.25 (s, 9H), 0.93 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 167.7, 149.9, 146.7, 133.0, 77.1, 64.19, 55.21, 49.6, 39.1, 30.9, 30.0, 22.3. MS (ESI): m/z calc’d for C17H26BN2O6S2: 429.1325 [M-H]-; found: 429.1336. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; diisopropyl-carbodiimide In methanol at 0 - 20℃; for 24.3h; | 2 Synthesis of Block -1 Tris (2-aminoethyl) amine (5.3 mL, 54 mmol, 2 eq.) Was dissolved in 100 mL MeOH.N-Methyliminodiacetic acid (4.0 g, 27 mmol, 1 eq.) Was dissolved in MeOH (35 mL) while slowly adding triethylamine (5 mL) in a separate flask.N, N'-Diisopropylcarbodiimide (DIC) (8.4 mL, 54 mmol, 2 eq.) Was then slowly added under ice-cooling and the solution was stirred at 0 ° C for 15 min.The activated diacetic acid solution was transferred into a dropping funnel and slowly added to the amine solution with vigorous stirring.After the addition was complete, the solution was stirred at room temperature for 24 hours.The solvent was then removed in vacuo and the Block-1 crude product was precipitated twice from MeOH-Et2O. (* Yield: 95%, melting point: 98 |
With triethylamine; diisopropyl-carbodiimide In methanol at 0 - 20℃; for 24.25h; | 2 (2) Synthesis of Block-1 Tris (2-aminoethyl) amine (5.3 mL, 54 mmol, 2 eq.) was dissolved in 100 mL MeOH. N-Methyliminodiessigesäure (4.0 g, 27 mmol, 1 eq.) was dissolved in MeOH (35 mL) while slowly adding triethylamine (5 mL) in a separate flask. Next, N, N'-Diisopropylcarbodiimide (DIC) (8.4 mL, 54 mmol, 2 eq.) Was slowly added under ice- The solution was stirred at 0°C for 15 minutes. The activated diacetic acid solution was transferred into a dropping funnel and slowly added to the amine solution with vigorous stirring. After the addition was complete, the solution was stirred at room temperature for 24 hours. The solvent was then removed in vacuo and the Block-1 crude product was precipitated twice from MeOH-Et2O. (*Yield: 95%, melting point: 98°C ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.2% | To a solution of <strong>[630120-99-9]5-(benzyloxy)-2-bromopyridine</strong> (98 g, 371 mmol) and triisopropyl borate (77 g, 408 mmol) in THF (800mL) was added n- butyllithium (193 mL, 482 mmol) at -78 C and stirred for 20 min at -78C. Then, the reaction mixture was stirred at rt for 3 h. The reaction mixture was added to a solution of 2,2'-(2,2'-(methylazanediyl)diacetic acid (109 g, 742 mmol) in DMSO (800 mL) at 115- 120 C (internal temperature). Then, the THF and DMSO was distilled off over 2 h to remove as much solvent as possible. The reaction flask was cooled, diluted with 3000 mL of ethyl acetate and washed with water (2000 mL x2), dried and concentrated. The residue was purifeid by silica gel chromatography to give 2-(5-(benzyloxy)pyridin-2-yl)-6-methyl- l,3,6,2-dioxazaborocane-4,8-dione (41 g, 120 mmol, 32.2 % yield) as pale solid. | |
21% | To a dry 250 mL round bottom flask equipped with a large stir bar and charged with <strong>[630120-99-9]5-(benzyloxy)-2-bromopyridine</strong> (2 1.8527 g, 83 mmol) was added THF (150 ml) and triisopropyl borate (19.40 ml, 84 mmol). The flask was sealed with a rubber septum, thenthe solution was sparged with N2 for 5 mm. The flask was cooled in a -78 C bath. To the solution was added dropwise over 30 mm n-butyllithium in hexanes (33.4 ml, 84 mmol). The cold bath was removed and the solution was allowed to slowly warm to r.t. with stirring. After 2 h the solution was transferred to a pressure-equalizing addition funnel. The addition funnel was fitted onto the center neck of a 3-neck 250 mL flask equippedwith a large stir bar was charged with N-methyliminodiacetic acid (24.35 g, 165 mmol) | |
21% | To a dry 250 mL round bottom flask equipped with a large stir bar and charged with <strong>[630120-99-9]5-(benzyloxy)-2-bromopyridine</strong> (21.8527 g, 83 mmol) was added THF (150 ml) and triisopropyl borate (19.40 ml, 84 mmol). The flask was sealed with a rubber septum, then the solution was sparged with N2 for 5 min. The flask was cooled in a -78 C bath. To the solution was added dropwise over 30 min n-butyllithium in hexanes (33.4 ml, 84 mmol). The cold bath was removed and the solution was allowed to slowly warm to r.t. with stirring. After 2 h the solution was transferred to a pressure-equalizing addition funnel. The addition funnel was fitted onto the center neck of a 3-neck 250 mL flask equipped with a large stir bar was charged with N-methyliminodiacetic acid (24.35 g, 165 mmol) and DMSO (150 ml). A side neck was fitted with a thermocouple. The other side neck was fitted with a water-cooled short-path distillation apparatus collecting into a 250 mL round bottom flask and vented to a bubbler. The addition funnel was capped with a gas adapter connected to a low-volume stream of N2 gas. The 3-neck flask was heated with an oil bath (150 C). Once the DMSO solution had reached 115-120 C the boronate solution was added dropwise at a rate necessary to maintain an internal temp of 115-120 C. The blue boronate solution immediately becomes a red/amber color upon contacting the DMSO solution. The reaction mixture is a deep amber solution. Upon completion of the addition the receiver flask containing THF was exchanged for an empty 200 mL round bottom flask. The bubbler line connected to the vacuum arm of the distillation apparatus was exchanged for a controlled vacuum source. The N2 source feeding into the addition funnel was closed. The system was placed under vacuum, slowly ramping to 30 Torr. The receiver flask was emptied, then the vacuum was slowly ramped to 2 Torr. The bath temperature was set to 125 C and the pressure was maintained at 2 Torr. When the majority of DMSO had been removed the flask was opened to ambient atmosphere. To the flask was added MeCN (100 mL). Heating was maintained until the solvent had reached reflux, then heating was stopped. To the hot mixture was added celite. The mixture was concentrated in vacuo to afford a clumpy solid which was subjected to S1O2 chromatography (EtOAc:MeCN 100:0 -> 0: 100) to afford the desired product as a colorless solid. This material was dissolved/suspended in MeCN (100 mL), then was diluted with Et20 (400 mL). The crystalline solid was collected via vacuum filtration. The solids were dried under high vacuum to afford (5-(benzyloxy)pyridin-2-yl)boronic acid MIDA ester as a colorless, fine crystalline solid (5.81 g, 21%). NMR (500 MHz, ACETONITRILE-di) d 8.50 - 8.42 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.44 - 7.38 (m, 2H), 7.38 - 7.33 (m, 1H), 7.31 (dd, J=8.4, 2.9 Hz, 1H), 5.16 (s, 2H), 4.10 - 4.04 (m, 2H), 3.98 - 3.92 (m, 2H), 2.54 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 85% | General procedure: In a Kitasato flask, Cu2CO3(OH)2 (0.25 mmol) was reacted with0.5 mmol of the corresponding iminodiacetic-like acids H2IDA (1,4,11),H2MIDA (5,10,12), H2EIDA (13), H2FurIDA (8), H2NBzIDA (6,14),H2MEBIDA (15), H2CBIDA (2,9,16) and H2NamIDA (3,7) in 60 mL ofdistilled water with heating (50 C), stirring and moderate vacuum.Once a clear blue solution of the binary chelate was obtained, thecorresponding Meade ligand (0.5 mmol) was added: 1Meade (1-3),3Meade (4-9), 7Meade (10), 9Meade (11-16). The solution was leftreacting for one hour. Afterwards, it was filtered in a crystallizationdevice (to remove possible un-reacted materials) and stood at r.t. coveredwith a plastic film to control the evaporation of the solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.2% | Stage #1: N-methyliminodiacetic acid; 2,6-diisopropylphenol With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: With hydrogenchloride In water | 1 Example 1 N-methyliminodiacetic acid (CAS: 4408-64-4)1.47 g and 1.78 g of propofol were dissolved in 30 mL of N,N-dimethylformamide, and 2.06 g of N,N-dicyclohexylcarbodiimide (DCC) was added,Stir for 2 hours at room temperature, filter, evaporate DMF under reduced pressure,Add 50 mL of 2N hydrochloric acid to the residue, filter,The filtrate was evaporated to dryness under reduced pressure,The residue was subjected to column chromatography to obtain 1.92 g of a white solid, which was Compound 1, the yield: 55.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethyl orthoformate In dimethyl sulfoxide at 100℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With orthoformic acid triethyl ester In dimethyl sulfoxide at 100℃; for 48h; Inert atmosphere; | 4.6 8-(6-(2,4-Dimethoxybenzyl)-7-oxo-6-azabicyclo[3.2.1]oct-2-en-2-yl)-4-methyldihydro-4λ 4,8λ 4-[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborole-2,6(3H,5H)-dione 1 A solution of enol triflate 9 (1.98 g, 4.70 mmol, 1.0 eq), PdCl2(PPh3)2 (97 mg, 0.14 mmol, 0.03 eq), PPh3 (73 mg, 0.28 mmol, 0.06 eq), KOPh (931 mg, 7.05 mmol, 1.5 eq) and B2pin2 (1.31 g, 5.17 mmol, 1.1 eq) in toluene (30 mL) under Ar was stirred and heated at 50 °C for 16 h. The solids were removed by filtration through Celite and the filtrate was evaporated under reduced pressure to give the crude pinacol boronate. The crude pinacol boronate was dissolved in DMSO (24 mL) and MIDA (4.49 g, 30.54 mmol, 6.5 eq) and HC(OEt)3 (3.70 mL, 21.14 mmol, 4.5 eq) were added. The resulting mixture was stirred and heated at 100 °C under Ar for 48 h. Saturated NH4Cl(aq) (10 mL) was added and the mixture was extracted with EtOAc (4×30 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and evaporated under reduced pressure to give the crude product. Purification by flash column chromatography on silica with 9:1 to 7:3 CH2Cl2-acetone as eluent gave vinyl MIDA boronate 1 (1.40 g, 70 %) as an off-white crystalline solid, mp 80-82 °C; RF (4:1 CH2Cl2-acetone) 0.29; IR (ATR) 2958, 1760 (C=O, ester), 1673 (C=O, amide), 1614, 1508, 1457, 1292, 1180, 1036, 823cm-1; 1H NMR (400 MHz, d6-acetone) δ 7.08 (d, J=8.5Hz, 1H, Ar), 6.53 (d, J=2.5Hz, 1H, Ar), 6.45 (dd, J=8.5, 2.5Hz, 1H, Ar), 5.98 (ddd, J=3.0, 3.0, 3.0Hz, 1H,=CH), 4.41 (d, J=15.0Hz, 1H, NCHH′), 4.27-4.07 (m, 4H, NCHH′, CHH’CO2), 3.96 (d, J=17.0Hz, 1H, CHH’CO2), 3.81 (s, 3H, OMe), 3.78-3.71 (m, 4H, OMe, NCH), 2.84 (s, 3H, NMe), 2.64 (d, J=4.5Hz, 1H, CH-5), 2.24-2.17 (m, 2H, CHH′-2), 2.16 (ddd, J=10.5, 5.5, 4.5Hz, 1H, CHH′-4), 1.67 (d, J=10.5Hz, 1H, CHH′-4); 13C NMR (100.6 MHz, d6-acetone) δ 177.0 (C=O, amide), 169.2 (C=O, ester), 167.9 (C=O, ester), 160.7 (ipso-Ar), 158.6 (ipso-Ar), 134.1 (=CH), 130.0 (Ar), 117.8 (ipso-Ar), 104.6 (Ar), 98.2 (Ar), 62.0 (CH2CO2), 61.3 (CH2CO2), 55.0 (OMe), 54.8 (OMe), 54.3 (NCH), 45.8 (NMe), 41.8 (CH-5), 37.6 (NCH2), 33.7 (CH2-4), 28.8 (CH2-2, only resolved in DEPT-135) (=C-B resonance not resolved); HRMS (ESI) m/z calcd for C21H25BN2O7 (M+Na)+ 451.1647, found 451.1654 (-0.2 ppm error). After chromatography (if necessary), vinyl MIDA boronate 1 can be further purified by recrystallisation from EtOAc to give 1 as colourless microcrystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In dimethyl sulfoxide; benzene at 105℃; Inert atmosphere; |
Tags: 4408-64-4 synthesis path| 4408-64-4 SDS| 4408-64-4 COA| 4408-64-4 purity| 4408-64-4 application| 4408-64-4 NMR| 4408-64-4 COA| 4408-64-4 structure
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P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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