Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 18680-27-8 | MDL No. : | MFCD00077851 |
Formula : | C10H18O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MOILFCKRQFQVFS-OORONAJNSA-N |
M.W : | 170.25 | Pubchem ID : | 10219606 |
Synonyms : |
(1S,2S,3R,5S)-(+)-Pinanediol
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 48.06 |
TPSA : | 40.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.53 cm/s |
Log Po/w (iLOGP) : | 2.14 |
Log Po/w (XLOGP3) : | 1.14 |
Log Po/w (WLOGP) : | 1.16 |
Log Po/w (MLOGP) : | 1.52 |
Log Po/w (SILICOS-IT) : | 1.35 |
Consensus Log Po/w : | 1.46 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.61 |
Solubility : | 4.14 mg/ml ; 0.0243 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.58 |
Solubility : | 4.44 mg/ml ; 0.0261 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.11 |
Solubility : | 13.2 mg/ml ; 0.0774 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.98 |
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 |
---|---|---|
95% | at 40℃; for 8 h; | The (+) – Pinanediol (17.0g,0.10mol) with 2-methylpropylBoric acid(11.2g,0.11mol) sequentially added into 200ml of Ethylene ether then themixture was heated to 40 ° C, stirred for 8 hours; after Completion of thereaction, the mixture was dried using anhydrous magnesium sulfate; filtrated;The filtrate was concentrated under reduced pressure to dryness; With 200mLisopropyl ether beating of the reaction for two hours; again filteredthen filtrate was concentrated under reduced pressure to dryness to obtainformula 3 compound 22.4g (0.095mol, Molar yield 95percent). |
94% | at 20℃; for 24 h; | A mixture of (+) -pinanediol (23.9 g, 0.140 mol) and 2- methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluting with hexane: ethyl acetate 90: 10 mixture. The product was obtained as a clear oil (32.6 g, 94percent yield). 1H NMR (DMSO-d6) : 4. 28 (1H, dd, J=8.8 Hz, 2.0) ; 2.30 (1H, M) ; 2.18 (1H, M) ; 1.96 (1H, t, J=5.3) ; 1.86 (1H, M) ; 1.78 (1H, set, J=6.8) ; 1.68 (1H, M) ; 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6) ; 0.81 (3H, s); 0.69 (2H, M). |
94% | at 20℃; for 24 h; | A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and 2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24 h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluding with hexane:ethyl acetate 90:10 mixture. The product was obtained as a clear oil (32.6 g, 94percent yield). 1H NMR (DMSO-d6): 4.28 (1H, dd, J=8.8 Hz, 2.0); 2.30 (1H, m); 2.18 (1H, m); 1.96 (1H, t, J=5.3); 1.86 (1H, m); 1.78 (1H, set, J=6.8); 1.68 (1H, m); 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6); 0.81 (3H, s); 0.69 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; osmium(VIII) oxide; trimethylamine-N-oxide; In tert-butyl alcohol; for 24h;Inert atmosphere; Reflux; | Under nitrogen protection conditions,To 100 mL of tert-butanol was added Me3NO 2H2O (11 g, 102 mmol)(+) - alpha-pinene (15 mL, 97 mmol) was added successively with stirring,Pyridine (7 mL) and osmium tetroxide (51 mg, 0.2 mmol)And then heated to reflux, 24 hours after the TLC test showed complete reaction,The reaction was reduced to room temperature and NaHSO3 (1.2 g, 12 mmol)The mixture was stirred for 1 hour, the reaction solution was transferred to a separatory funnel, the organic phase was separated,The aqueous phase was extracted with ether (3 x 20 mL), the organic phases were combined,Add anhydrous sodium sulfate drying, drying and filtering, Using a rotary evaporator in addition to solvent, column chromatography separation (petroleum ether:Ethyl acetate = 30: 1) to give 15 g of a white solid in 91% yield. |
83% | With pyridine; osmium(VIII) oxide; trimethylamine-N-oxide; In water; tert-butyl alcohol; for 24h;Reflux; | This compound was synthesized according to previously reported method.1 To a mixture of (+)-alpha-pinene (15.4 mL, 96.9 mmol), trimethylamine oxide dihydrate (11.3 g, 102 mmol), pyridine (8.0 mL, 0.1 mmol), water (16 mL), and t-butyl alcohol (74 mL) was added osmium tetraoxide (100 mg, 0.39 mmol). The reaction was refluxed for 24 h. After cooling, sodium bisulfite (1.2 g, 11.5 mmol) was added and the resulting mixture was stirred for 10 min, and the aqueous phase was extracted with ether (3 × 20 mL). The combined organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to yield 13.7 g (83% yield) of (+)-pinanediol 13 as a white solid. 1H NMR (CDCl3, 400 MHz) delta 3.97 (m, 1H), 2.98 (s, 2H), 2.45 (m, 1H), 2.17 (m, 1H), 1.99 (t, 1H, J=5.8Hz), 1.90 (m, 1H), 1.62 (m, 1H), 1.35 (d, 1H, J=10.4Hz), 1.28 (s, 3H), 1.25 (s, 3H), 0.92 (s, 3H). MS (ESI) m/z 193.1 [M + Na]+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98 % Chromat. | With 3,3-dimethyldioxirane In dichloromethane; acetone at 0℃; for 4h; | |
19.2 g | With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at 10 - 20℃; for 2.5h; | 1.2.2 Step 2.2: (1R,2R,5R)-(+)-2-Hydroxy-3-Pinanone Step 2.2: (1R,2R,5R)-(+)-2-Hydroxy-3-Pinanone Triethylamine (Et3N) (80.2 mL; 0.58 mol) was added to a solution of (1R,2R,3S, 5R)-(-)-Pinanediol (24.5 g; 143.9 mmol) in a dimethyl sulfoxide/methylene chloride solvent mixture (154 mL; 1/1) at 10° C. SO3.Pyridine (68.7 g; 0.43 mol) was then added portion-wise over 30 minutes while the temperature was maintained below 20° C. The reaction mixture was stirred for 2 hours at 10° C. then diluted with ethyl acetate (300 mL). The organic layer was washed with HCl 0.5 N (2*150 mL), brine (150 mL), then dried over MgSO4 and filtered. The solvents were removed under vacuum to give a brown oil. The crude product was purified by flash chromatography on silica gel (methylcyclohexane-ethyl acetate: 9/1) to give the title compound as a yellow oil (19.2 g; 63% over two steps). GC: tr=10.9 min; Distillation: B.p=100-104° C. (3-4 mmHg) 1H NMR (400 MHz, CDCl3): 0.90 (s, 3H); 1.30 (s, 3H); 1.40 (s, 3H); 1.70 (d, 1H, J=12.0 Hz); 2.10 (m, 2H); 2.30 (s, 1H); 2.50 (m, 1H); 2.60 (brs, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In diethyl ether; pentane at 20℃; for 6h; | |
98% | In diethyl ether; pentane equimolar amts., stirring in pentane/ether=10:1 at room temp. for 6 h; solvent removal (reduced pressure), distn. (61°C, 0.1 Torr); | |
92% | In diethyl ether (+)-α-pinanediol and CH2=CHB(OBu)2 were stirred in ether overnight under Ar; soln. was concd., residue distilled in the presence of galvinoxyl free radical; elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In tetrahydrofuran for 0.333333h; Inert atmosphere; | VII.B.2 (+)-Pinanediol methaneboronate (GBS27). A solution of (+)-pinanediol (2.845 g, 16.71 mmol) and methylboronic acid (1.00 g, 16.71 mmol) in THF (15 mL) was stirred for 20 min, concentrated, and then purified by chromatography (light petroleum/diethyl ether 9: 1), affording GBS27 as a colourless oil (3.07 g, 95% yield). [a]D +31.3 (c 1.1, MeOH). XH-NMR (400 MHz, CDC13): δ 0.31 (3H, s, BCH3), 0.87 (3Η, s, pinanyl CH3), 1.15 (1Η, d, J 10.9, pinanyl Hendo), 1-32 (3Η, s, pinanyl C¾), 1.47 (3Η, s, pinanyl G¾), 1.85-2.39 (5Η, m, pinanyl protons), 4.28 (1Η, dd, J 8.7, 1.8, CHOB). 13C-NMR (100 MHz, CDC13): δ -6.2 (br, CB), 24.0, 26.3, 26.5, 27.1, 28.7, 35.5, 38.1, 39.5, 51.3, 85.4. GC-MS, m/z: 194 (9%, M+), 179 (59%), 153 (30%), 137 (27%), 125 (base peak), 119 (15.5%), 111 (59%), 98 (71%), 91 (17.5%), 83 (92%), 77 (19%), 67 (57%), 55 (45%), 43 (57%). |
93% | In diethyl ether | |
In diethyl ether at 20℃; |
In diethyl ether at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In diethyl ether; at 23℃; for 16h;Inert atmosphere; | Into a 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was weighed isopropyl boronic acid (12.5 g, 142 mmol, 1.1 equiv). The solid was taken up in diethyl ether (100 mL), affording a yellow suspension. To this suspension was added over 4 equal portions (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3 .1.1 ]heptane-2,3 -diol (22.0 g, 129 mmol, 1.0 equiv) [NOTE: Slight exotherm observed]. The resulting yellow suspension became a light white opaque solution. The reaction mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the crude yellow oil poured onto a pad of silica gel (10 cm wide x 6 cm high) on a sintered glass funnel and the product eluted with 2% EtOAc in hexanes (500 mL). The clear filtrate was concentration under reduced pressure to afford a clear oil (23.7 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In diethyl ether at 20℃; | |
71% | In diethyl ether at 20℃; | |
71% | In diethyl ether portionwise adding of pinanediol to ether soln. of boronic acid deriv. in ether at room temp.; rotary evapn. under reduced pressure, chromy. (silica gel,light petroleum-ethyl acetate 80:20); elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In diethyl ether at 20℃; | 8.1 Step 1: Synthesis of phenylboronic acid-(1S,2S,3R,5S)-(+)-2,3-decanediol ester (F-2) Compound F-1 phenylboronic acid (lg, 8 · 20 mmol) was dissolved in diethyl ether (20 mL).After adding (IS, 2S, 3R, 5S)-(+)-2,3-decanediol (1.4 g, 8.20 mmol), it was allowed to react at room temperature overnight. The reaction mixture was washed twice with water and then brine, brinePurified by silica gel column chromatography (eluent: PE/EtOAc = 100:1)Obtained 1.96 g of white solid product, yield 93% |
91% | With magnesium sulfate In diethyl ether | |
90% | With 1H-imidazole; iron(III) chloride In water; acetonitrile at 20℃; for 0.5h; Inert atmosphere; | 2.2. General Procedure B : Transformation of Boronic Acids into Boronates General procedure: To a solution of aryl boronic acid (1 mmol) in MeCN (4 mL) was added, sequentially, asolution of FeCl3 (8 mg, 0.05 mmol, 5 mol%) in H2O (1 mL), imidazole (204 mg, 3 mmol)and pinacol (118 mg, 1 mmol). The resulting cloudy orange mixture was stirred at roomtemperature for 30 min. The reaction was then diluted with H2O (5 mL) and extracted withEt2O (3 x 8 mL). The combined organic extracts were dried (Na2SO4) and concentrated invacuo. The resulting oil was then purified by a filtration through a silica gel plug (eluting withEt2O), affording the title compound. |
88% | In tetrahydrofuran for 0.166667h; | |
88% | In tetrahydrofuran for 0.166667h; | 2; 8 (+)-pinanediolphenylboronate (19). A solution of (+)-pinanediol (665 mg, 3.9 mmol) and phenylboronic acid (18) (476 mg, 3.9 mmol) in THF (5 mL) was stirred for 10 min, concentrated and distilled to yield 21 (879 mg, 88%) bp 135° C. (1.5 mmHg) as a viscous colorless oil which solidified on standing, mp 50° C., []D=+14.9 (c 2.3, CHCl3). IR (KBr): 2910, 1361, 1094, 701 cm-1. 1HNMR (CDCl3): δ 0.92 (3H, s, pinanyl CH3), 1.25 (1H, d, J=10.5 Hz, pinanyl Hendo), 1.34 (3H, s, pinanyl CH3), 1.50 (3H, s, pinanyl CH3), 1.9-2.6 (5H, m, pinanyl protons), 4.48 (1H, dd, J=8.8, 2.0 Hz, pinanyl CHOB), 7.34-7.54 (3H, m, Hm-Hp), 7.85 (2H, dd, J=7.9 Hz, 1.6, Ho). 13C NMR (CDCl3): δ 24.4, 26.9, 27.5, 29.1, 36.0, 38.6, 40.0, 51.9, 78.7, 86.6, 128.1, 131.5, 135.2. Aromatic CB not seen. EI-MS: m/z 256 (M+), 241, 215, 187, 173, 108 (base peak), 93, 77. Anal. Calcd for C16H21BO2: C, 75.02; H, 8.26. Found: C, 74.77; H, 8.53. |
In diethyl ether at 20℃; | ||
In diethyl ether at 25℃; for 7h; | General procedure: At 25, boronic acids4a-4c(98.10 mmol) was dissolved in 150 mLether, (+)-pinanediol was at once. The reaction was stired at room temperature and determined by TLC analysis. Concentration and flash chromatography over silica gel (EtOAC: petroleum 1:40) produced5a-5c, yields 94%-97%. | |
In diethyl ether at 20℃; Inert atmosphere; | ||
With water In acetonitrile at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In diethyl ether; at 40℃; for 8h; | The (+) - Pinanediol (17.0g,0.10mol) with 2-methylpropylBoric acid(11.2g,0.11mol) sequentially added into 200ml of Ethylene ether then themixture was heated to 40 C, stirred for 8 hours; after Completion of thereaction, the mixture was dried using anhydrous magnesium sulfate; filtrated;The filtrate was concentrated under reduced pressure to dryness; With 200mLisopropyl ether beating of the reaction for two hours; again filteredthen filtrate was concentrated under reduced pressure to dryness to obtainformula 3 compound 22.4g (0.095mol, Molar yield 95%). |
94% | In diethyl ether; at 20℃; for 24h; | A mixture of (+) -pinanediol (23.9 g, 0.140 mol) and 2- methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluting with hexane: ethyl acetate 90: 10 mixture. The product was obtained as a clear oil (32.6 g, 94% yield). 1H NMR (DMSO-d6) : 4. 28 (1H, dd, J=8.8 Hz, 2.0) ; 2.30 (1H, M) ; 2.18 (1H, M) ; 1.96 (1H, t, J=5.3) ; 1.86 (1H, M) ; 1.78 (1H, set, J=6.8) ; 1.68 (1H, M) ; 1.30 (3H, s); 1.25 (3H, s); 1.01 (1H, d); 0.9 (6H, d, J=6.6) ; 0.81 (3H, s); 0.69 (2H, M). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at 25℃; for 7h; | General procedure: At 25, boronic acids4a-4c(98.10 mmol) was dissolved in 150 mLether, (+)-pinanediol was at once. The reaction was stired at room temperature and determined by TLC analysis. Concentration and flash chromatography over silica gel (EtOAC: petroleum 1:40) produced5a-5c, yields 94percent-97percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.14 g | In tetrahydrofuran; diethyl ether; hexane at 20℃; | |
With n-butyllithium In tetrahydrofuran; diethyl ether; hexane at 20℃; | 1 (+)-pinanediol 3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenylboronate (7). n-BuLi (2.5 mL of a 2.5 M solution in hexane, 6.23 mmol) was added dropwise with stirring to a solution of 6 (1.51 g, 5.93 mmol) in THF (9.5 mL) at -78° C. under argon. After 30 min a solution of trimethylborate (0.7 mL, 5.93 mmol) in THF (2 mL) was added and the mixture stirred for 1.5 h; thereafter, the resulting yellow solution was quenched with TMSCl (0.75 mL, 5.93 mmol) and allowed to reach rt. After 1 h (+)-pinanediol (1.01 g, 5.93 mmol) dissolved in a minimum amount of anhydrous Et2O was added one portion to the solution, and then stirred overnight. The reaction mixture was partitioned in Et2O (16 mL) and H2O (10 mL) and the aqueous phase extracted with Et2O (2×10 mL). The combined organic phases were dried on MgSO4, filtered and concentrated to give an orange oil, which was purified by chromatography (7:3 EtPet/EtOAc) and crystallization (EtPet), affording 7 (1.14 g, 54%) as a white crystalline solid, mp 98-101° C., [α]D=+11.2 (c 1.5, CHCl3). IR (KBr): 1646 cm-1. 1H NMR (CDCl3): δ 0.81 (3H, s, pinanyl CH3), 1.22 (1H, d, J=10.5 Hz, pinanyl Hendo), 1.33 (3H, s, pinanyl CH3), 1.40 (6H, s, 2CH3), 1.50 (3H, s, pinanyl CH3), 1.5-2.5 (5H, m, pinanyl protons), 4.22 (2H, s, CH2O), 4.47 (1H, dd, J=8.8, 2.0 Hz, pinanyl CHOB), 7.43 (1H, t, J=7.7 Hz, H5 arom.), 7.92 (1H, dt, J=7.7, 1.5 Hz, H6 arom.), 8.05 (1H, dt, J=7.7, 1.5 Hz, H4 arom.), 8.43 (1H, br s, H2 arom.). 13C NMR (CDCl3): δ 24.4, 26.9, 27.5, 28.8 (2C), 29.1, 35.9, 38.6, 40.0, 51.9, 68.0, 78.8, 79.5, 86.8, 128.1, 131.2, 135.0, 137.8, 162.5, (CB and aromatic quaternary C not seen). EI-MS: m/z 353 (M+), 338 (base peak), 323, 282, 242, 202, 186, 130, 103, 67, 55. Anal. Calcd for C21H28NO3B: C, 71.39; H, 7.99; N 3.96. Found: C, 71.01; H, 8.65; N, 3.89. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dichloromethane at 0 - 20℃; | Synthesis of 2-isopropoxy-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborole Synthesis of 2-isopropoxy-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaboroleTo a stirred at 0° C. solution of (1S,2S,3R,5S)-(+)-pinanediol (or (1R,2R,3S,5R)-(-) pinanediol) in dichloromethane, triisopropylborate (1 equiv.) was added and then the reaction was allowed to warm up to room temperature overnight. The reaction was concentrated under reduced pressure to obtain the product as clear oil in quantitative yield. For (1S,2S,3R,5S)-(+)-pinanediol derivative in chloroform [D]20c=0.1=-18.16, 1H NMR (400 MHz, CDCl3): δ 4.36-4.29 (m, 1H), 4.25-4.23 (m, 1H), 2.34-2.26 (m, 1H), 2.25-2.18 (m, 1H), 2.03-1.99 (m, 1H), 1.92-1.82 (m, 2H), 1.39-1.36 (m, 4H), 1.26 (s, 3H), 1.19 (d, J=6.3 Hz, 6H), 0.81 (s, 3H). 11B NMR (128.3 MHz, CDCl3): δ 22.0. 13C NMR (100.6 MHz, CDCl3): δ 84.4, 77.2, 67.7, 51.8, 39.7, 38.5, 36.0, 28.8, 27.3, 26.6, 24.6, 24.5, 24.20. For (1R,2R,3S,5R)-(-)-pinanediol derivative in chloroform [D]20c=0.1=19.44. |
93% | In toluene for 0.5h; Heating; | |
90% | In tetrahydrofuran at 0℃; for 2h; | A.2.1 To a solution of (1S, 2S, 3R, 5S)- (+)-Pinanediol (50.0 g, 0.293 mol) in anhydrous tetrahydrofuran (350 ml) triisopropoxy borane was slowly added while stirring at 0°C under nitrogen. After 2h the solvent was removed by rotary evaporation. The oily residue was redissolved in hexane (150 ml) and the solution was filtered to remove a very small amount of a white solid. The filtrate was concentrated by rotary evaporation affording the product as a clear oil (62.6 g, 90% yield). 'H NMR (DMSO-d6): 4.31-4. 20 (2H, M) ; 2.34-2. 16 (2H, M) ; 1.96 (1H, t, J=5.5) ; 1.90- 1.85 (1H, M) ; 1.74-1. 67 (1H, M) ; 1.32 (3H, s); 1.31 (1H, d, J=7.6) ; 1.25 (3H, s); 1.14 (3H, d, J=6.1) ; 1.13 (3H, d, J=6.1) ; 0.81 (3H, s). |
90% | In tetrahydrofuran at 0℃; for 2h; | A.2.1 Step 1: 2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole To a solution of (1S,2S,3R,5S)-(+)-pinanediol (50.0 g, 0.293 mol) in anhydrous tetrahydrofuran (350 ml) triisopropoxy borane was slowly added while stirring at 0° C. under nitrogen. After 2 h the solvent was removed by rotary evaporation. The oily residue was redissolved in hexane (150 ml) and the solution was filtered to remove a very small amount of a white solid. The filtrate was concentrated by rotary evaporation affording the product as a clear oil (62.6 g, 90% yield). 1H NMR (DMSO-d6): 4.31-4.20 (2H, m); 2.34-2.16 (2H, m); 1.96 (1H, t, J=5.5); 1.90-1.85 (1H, m); 1.74-1.67 (1H, m); 1.32 (3H, s); 1.31 (1H, d, J=7.6); 1.25 (3H, s); 1.14 (3H, d, J=6.1); 1.13 (3H, d, J=6.1); 0.81 (3H, s). |
In dichloromethane at 0 - 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In tetrahydrofuran at 20℃; for 18h; Inert atmosphere; | 4 Example 4:Dichloro methylene boronic acid - (+) - α-pinane diol ester(Compound III-5-a)Of the preparation Compound No. III-3 of Example 2 was added to 150 mL of anhydrous tetrahydrofuran(10 g, 63 mmol) and Example 3 Compound III-4-a (7.2 g, 42 mmol)At room temperature, the TLC assay showed complete reaction after 18 hours,The use of rotary evaporator in addition to solvent,Column chromatography separation (petroleum ether: ethyl acetate = 10: 1)To give 10 g of a colorless oily liquid in a yield of 91% |
In tetrahydrofuran at 20℃; | ||
4.92 g | In diethyl ether at 20℃; for 18h; |
In tetrahydrofuran at 20℃; | ||
4.8 g | In diethyl ether at 20℃; for 24h; | A solution of the crude product 15 (6.3 g, 0.04 mmol) and (+)-pinanediol (3.4 g, 0.02 mmol) in 100 mL ether was stirred at rt for 24 h. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to yield 4.8 g (91% yield) of (+)-pinanediol dichloromethaneboronate 16 as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 5.39 (s, 1H), 4.46 (d, 1H, J=8.8Hz), 2.33 (m, 2H), 2.12 (t, 1H, J=5.2Hz), 1.94 (m, 2H), 1.46 (s, 3H), 1.30 (s, 3H), 1.21 (d, 1H, J=11.2Hz), 0.84 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine at 20℃; Inert atmosphere; | Synthesis of PiTs (1S,2S,3R,5S)-(+)-Pinanediol (3.61 g, 21.2 mmol) and 20 mL anhydrous pyridine were placed in a 50 mL round bottomed flask and stirred under nitrogen. Next, p-Toluenesulfonyl chloride (4.45 g, 23.3 mmol) was added to the mixture, which was stirred overnight at room temperature. The reaction mixture was poured into 200 mL deionized water and the product was extracted into ethyl acetate (3×75 mL). The combined organic layers were quickly washed with 10% hydrochloric acid (3×), deionized water (2×), saturated aqueous sodium bicarbonate, and brine and then dried over anhydrous magnesium sulfate. After filtering, 5 g of basic alumina was added and the slurry was stirred for 1 hour. The alumina was removed by filtration and the solution was rotary evaporated to dryness to yield 6.38 g of crystals (93% yield) of pinane tosylate (PiTs). 1H-NMR (CDCl3) (δ, ppm): 7.86 (d, 2H, ArH), 7.39 (d, 2H, ArH), 4.92-4.87 (m, 1H, CH-OTs), 2.48 (s, 3H, CH3), 2.28-2.21 (m, 2H, C-H), 2.02 (m, 1H, C-H), 1.91 (m, 1H, C-H), 1.83 (m, 1H, C-H), 1.56 (m, 2H, CH), 1.28 (s, 3H, CH3), 1.23 (s, 3H, CH3), 0.94 (s, 3H, CH3) |
46% | With pyridine at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: Triisopropyl borate; 1,1-dibromomethane With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: With trimethylsilyl bromide In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Stage #3: pinanediol In tetrahydrofuran; hexane at 20℃; for 1h; Inert atmosphere; | VII.B.2 (+)-Pinanediol bromomethaneboronate (CR158). MW: 272.97. w-Butyllithium (2.5 M solution in w-hexane, 1 1.75 niL, 29.37 mmol) was added dropwise to a stirred solution of dibromomethane (2.26 mL, 32.45 mmol) and triisopropyl borate (6.5 mL, 27.97 mmol) in THF (20 mL) at -78 °C under argon atmosphere. After one hour bromotrimethylsilane (4.28 mL, 32.45 mmol) was slowly added at the same temperature. The mixture was allowed to gradually reach room temperature overnight. A solution of (15,,25',3R,55)-(+)-pinanediol (4.76 g, 27.97 mmol) in dry THF (10 mL) was then added at rt and left to react for 1 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (40 mL), and the aqueous phase was extracted with ethyl acetate (2 x 80 mL). The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude residue was purified by chromatography (light petroleum/ethyl acetate 9: 1), affording CR158 as a colourless oil (6.010 g, 79% yield). [a]D +22.5 (c 2.8, CHC13). ¾-NMR (200 MHz, CDC13): δ 0.80 (3H, s, pinanyl G¾), 1.16 (1H, d, J 1 1.0, pinanyl Hendo), 1.25 (3H, s, pinanyl CH3), 1.37 (3Η, s, pinanyl CH3), 1.71- 2.39 (5Η, m, pinanyl protons), 2.57 (2Η, s, BCH2), 4.32 (1Η, dd, J 8.7, 1.8, CHOB). 13C-NMR (50 MHz, CDCI3): δ 8.2 (br, CB), 23.9, 26.2, 27.0, 28.4, 35.2, 38.2, 39.3, 51.2, 78.5, 86.7. IR (neat): vmax 1242, 1340, 1416. GC-MS, m/z: 272-274 (1 : 1, M+, 1 1), 257-259 (1 : 1, 32), 231 (33), 216-218 (1 : 1, 30), 203-205 (1 : 1, 52), 189 (25), 176 (26), 152 (25), 134 (74), 1 19 (30), 109 (30), 96 (80), 83 (100), 81 (66), 67 (62), 55 (51). Anal. Calcd for CnH18BBr02: C, 48.40; H, 6.65. Found: C, 48.48; H, 6.71. |
63.7% | Stage #1: Triisopropyl borate; 1,1-dibromomethane With n-butyllithium; trimethylsilyl bromide In tetrahydrofuran at -78 - 20℃; Stage #2: pinanediol In tetrahydrofuran at 20℃; for 4h; | 64.3 Step 3. Synthesis of (((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)methyl)zinc(II) iodide. To a solution of dibromomethane (47.20 g, 271 mmol) and triisopropyl borate (39.85 g, 212 mmol) in THF (200 mL) at -78oC under argon was added n-BuLi (2.5 M in hexane, 93.5 mL, 234 mmol) dropwise over 50 min. After the resulting mixture was stirred at -78oC for 1.5 h, bromotrimethylsilane (31 mL, 235 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. To the reaction mixture was then added (+)-pinanediol (36.03 g, 212 mmol) and stirred at room temperature for 4 h. The reaction mixture was then quenched with water, extracted with ethyl acetate (3x). The combined organic phase was dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by flash chromatography on silica gel (340 g column) eluted with 0 to 20% ethyl acetate/hexanes to afford 36.84 g (63.7%) of (3aS,4S,6S,7aR)-2-(bromomethyl)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborole as a clear liquid. ESI-MS m/z 273.1, 275.0 (M+H)+. |
With n-butyllithium; trimethylsilyl bromide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | In n-heptane at 20℃; for 2h; | 3.4 Step 4: Synthesis of 1,1-d2-2-methylpropylboronic acid-(+)-pinanediol ester (Compound 22). The compound 21 (110 mg, 1.06 mmol) and (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol (179.8 mg, 1.06 mmol) were added to a reaction flask, and dissolved by adding 3 mL of n-heptane. The reaction was stirred at room temperature for 2 hours. After TLC detected the reaction was completed, the mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and dried in vacuo to give a product (238 mg, yield: 94.2%). |
With tert-butyl methyl ether at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In tert-butyl methyl ether; at 20℃; for 18.0h; | Example 1; Synthesis of (2R)-boroPro- (lS, 2S, 3R, 5S)-pinanediol ester, hydrochloride (2); [0280] A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (20 g, 117 mmol, 1 eq) and dry THF (60 mL) under a nitrogen atmosphere. The clear colorless solution was cooled to-78C and a solution of s- BuLi (100 mL of a 1.4 M solution in cyclohexane, 140 mmol) was added slowly over a 30 minute period. The light orange colored solution was stirred at-78C for 3 hours followed by treatment with B (OMe) 3 (39 mL, 350 mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0C. Upon reaching 0C, the reaction was quenched with a small amount of water (-2 mL), allowed to warm to room temp then extracted into 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL). The aqueous phase was acidified to pH 3 by the addition of 2 N HCl and then extracted with EtOAc (3 x 120 mL). The organic extracts were combined and dried over Na2SO4 and concentrated to produce the free boronic acid (22.08 g, 103 mmol) as a sticky white solid in 88% yield. Without further purification the boronic acid was dissolved in tert-butyl methyl ether (150 mL) and with constant stirring (+) -pinanediol (17.5 g, 103 mmol) was added at room temperature. After 18 hr the ether was removed and the (+) -pinanediol boronic ester was purified by column chromatography (silica gel, 1: 3 hexanes/EtOAc) to give a clear thick oil (26.84 g, 76.8 mmol, 76% yield, Rf= 0.6 using a 2: 1 hexane/ethyl acetate eluant, made visual via 12 and/or PMA stain). Removal of the Boc protecting group was achieved by dissolving the oil in dry ether, cooling to 0C in an ice bath and with constant stirring dry HCl (g) was bubbled into the solution for 10 minutes. After 2 hours a white precipitate developed in the flask and the ether and excess HCl were removed in vacuo to afford the racemic HCl salt as a white solid. Crystallization and isolation of the desired isomer was performed by dissolving the HCI salt in a minimal amount of dichloromethane (250 mL) with gentle heating to facilitate a homogenous solution followed by continuous stirring for 8 hours to yield a fluffy white precipitate that was collected by vacuum filtration, dried and then dissolved in minimal 2-propanol (-200 mL) with gentle heating until homogenous. The alcoholic solution was stirred over night and the resulting white precipitate was collected by vacuum filtration affording isomerically pure 1 as a white solid. (7.0 g, 27 mmol, 23% yield).'H NMR (400 MHz, D20) 8 4.28 (d, J= 8.0 Hz, lH), 3.06 (m, 3H), 2.18 (m, 1H), 1.96 (m, 2H), 1.78 (m, 3 H), 1.62 (m, 2H), 1.21 (s, 3H), 1.05 (m, 5H), 0.84 (d, J=12 Hz, 2H), 0.71 (s, 2H), 0.62 (s, 3H). |
12.1% | In ethyl acetate; at 20℃; for 18.0h; | General procedure: A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (10g, 58mmol, 1eq) and dry THF (40mL) under a nitrogen atmosphere. The clear colorless solution was cooled to -78C and a solution of s-BuLi (64mL of a 1.0M solution in cyclohexane, 64mmol) was added slowly over a 30min period. The light orange colored solution was stirred at -78C for 3h followed by treatment with B(OMe)3 (15mL, 175mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0C. Upon reaching 0C, the reaction was quenched with a small amount of water (?2mL), allowed to warm to room temp then extracted into 2N NaOH (100mL) and backwashed with additional EtOAc (60mL). The aqueous phase was acidified to pH 3 by the addition of 2N HCl and then extracted with EtOAc (3×60mL). The organic extracts were combined and dried over Na2SO4 and concentrated to produce the free boronic acid 9g as a sticky white solid. Without further purification the boronic acid was dissolved in EtOAc (60mL) and with constant stirring (+)-pinanediol (7.0g, 41mmol) was added at room temperature. After 18h the ester was removed and the (+)-pinanediol boronic ester was purified by column chromatography (silica gel, 6:1 hexanes/EtOAc) to give a clear thick oil (12.1g, 34.8mmol) 60% yield in two steps. 1H NMR (400MHz, CDCl3) delta 4.50-4.15 (m, 1H), 3.38 (dt, J=13.8, 6.1Hz, 2H), 3.12 (ddd, J=25.1, 15.8, 8.4Hz, 1H), 2.33 (dd, J=12.3, 10.3Hz, 1H), 2.20 (s, 1H), 2.10-1.69 (m, 7H), 1.45 (d, J=7.3Hz, 9H), 1.41 (s, 3H), 1.28 (s, 3H), 0.84 (s, 3H). |
2.52 g | In tert-butyl methyl ether; at 20℃; for 12.0h; | Free boric acid C1 of Example 1 (2.1 g, 9.36 mmol)Soluble in 20mL methyl tert-butyl ether,Add (+)-pinanediol (1.75 g, 10 mmol) at room temperatureStirring was continued, and the reaction was completed after 12 hours.The solvent was distilled off and directly subjected to column chromatography (petroleum ether: ethyl acetate = 10:1)A clear viscous oil of 2.52 g was obtained in a yield of 76%. |
331 g | With magnesium sulfate; In tetrahydrofuran; for 2.0h; | (1) N-Boc-2-pyrrolidine boronic acid (215g, 1mol) is dissolved in tetrahydrofuran (1.5L),Add anhydrous magnesium sulfate (240g, 2mol) with stirring,Was then added (1S, 2S, 3R, 5S) -2,3- pinanediol (170g, 1mol),After two hours of reaction, it was filtered, washed, and the organic phase was concentrated and dried.331 g gave intermediate A1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In trifluoroacetic acid at 30℃; for 0.1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In tetrahydrofuran; diethyl ether; hexane at 20℃; | 20c (+)-Pinanediol (3-Dimethoxymethyl)phenylboronate (23b). n-BuLi (5.72 mL of a 2.5 M solution in hexane, 14.3 mmol) was added dropwise with stirring to a solution of 22b (3.00 g, 13.0 mmol) in THF (8 mL) at -78° C. under argon. After 30 min, a solution of trimethylborate (1.50 mL, 13.0 mmol) in THF (4 mL) was added, and the mixture was stirred for 1.5 h. The resulting turbid solution was quenched with TMSCl (1.65 mL, 13.0 mmol) and allowed to reach rt. After 4 h a clear yellow solution is obtained and (+)-pinanediol (2.21 g, 13.0 mmol) dissolved in a minimum amount of anhydrous Et2O was added and stirred overnight. The reaction mixture was partitioned in Et2O (75 mL) and H2O (25 mL), and the aqueous phase was extracted with Et2O (3×25 mL). The combined organic phases were dried on MgSO4, filtered, and concentrated to give an orange oil, which was purified by gradient chromatography (9:1 to 7:3 EtPet/EtOAc), affording 23b (3.21 g, 75%) as a yellow liquid, [α]D=+7.80 (c 2.78, CHCl3). 1H NMR (CDCl3): δ 0.88 (3H, s, pinanyl CH3), 1.22 (1H, d, J=10.5 Hz, pinanyl Hendo), 1.30 (3H, s, pinanyl CH3), 1.47 (3H, s, pinanyl CH3), 1.8-2.6 (5H, m, pinanyl protons), 3.33 (6H, s, CH(OCH3)2), 4.44 (1H, dd, J=8.8, 1.8 Hz, pinanyl CHOB), 5.40 (1H, s, CH(OCH3)2), 7.37 (1H, t, J=7.6 Hz, H5 Ph), 7.55 (1H, d, J=7.6 Hz, H6 Ph), 7.78 (1H, d, J=7.6 Hz, H4 Ph), 7.90 (1H, s, H2 Ph). 13C NMR (CDCl3): δ 25.4, 27.9, 28.5, 30.1, 36.9, 39.6, 40.9, 52.8, 54.1, 79.7, 87.6, 104.7, 129.0, 130.8, 134.5, 136.3, 138.8 (CB and aromatic quaternary C not seen). EIMS: m/z 330 (M+), 315, 299 (base peak), 289, 261, 247, 203, 147, 121, 105, 93, 91, 83, 75, 67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: (Bromomethyl)cyclobutane With magnesium In diethyl ether for 1.16667h; Heating / reflux; Stage #2: With Triisopropyl borate In diethyl ether at 0 - 20℃; for 4h; Stage #3: pinanediol With sulfuric acid more than 3 stages; | 3 To a flame dried 2-necked round bottom flask equipped with a reflux condenser and magnetic stir bar charged with Et2O (15 mL) and Mg° (200 mg, 8.37 mmol, 1.25 eq.). The suspension was stirred under a blanket OfN2 and an ethereal solution of 5 (1.Og. 6.7 mmol) was slowly dripped into the flask until the suspension began to reflux. The remaining solution of 5 was added over a 10 min period and the reaction was heated at reflux for an additional 60 min. The resulting metallic grey suspension was cooled to rt, diluted with Et2O (50 mL) and slowly dripped into a O0C solution of triisopropyl borate (1.43 mL, 6.7 mmol) in Et2O (50 mL). The resulting cloudy solution was allowed to warm to rt and stirred for 4 hr followed by addition of 10% H2SO4 (50 mL). The biphasic solution was extracted with additional Et2O (2 x 30 mL), washed with H2O (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated to approx half the original volume followed by addition of (+)-pinanediol (1.14g, 6.7 mmol). The solution was stirred overnight, concentrated, and purified by flash column chromatography (silica gel, 1.5% EtOAc in hexanes) to give 6 (631 mg, 2.54 mmol, 38% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.23 (dd, IH); 2.48 (m, IH); 2.18 (m, IH); 2.10 (m, 2H), 2.04 (dd, IH); 1.9 (m, IH); 1.8 (m, 3H); 1.61 (m, 2H); 1.6 (s, 3H); 1.28 (s, 3H); 1.11 (d, IH); 1.0 (d, 2H); 0.85 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With n-butyllithium In diethyl ether at 20℃; for 1.5h; | 1.1 Step 1: (3aS,4S,6S)-2-(dichloromethyl)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborole Intermediate 1To a solution of DCM (80 mL, 1.2 mol) in THF (800 mL) at -80° C. to -90° C. was added n-BuLi (2.5 M in hexane, 480 mL, 1.2 mol) under N2, and the reaction mixture was stirred for 1.5 h below -80° C. B(OEt)3 (200 mL, 1.2 mol) was added in one portion and the mixture was stirred for 1 h at -45° C. to -30° C. Aqueous HCl (5 M, 240 mL, 1.2 mol) was then added dropwise while maintaining the temperature below -20° C. and the resulting mixture was stirred at -20° C. for 4 h. The organic layer was separated, and the water layer was extracted with diethyl ether (100 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give an intermediate. The intermediate was re-dissolved in diethyl ether (800 mL) and pinanediol (188 g, 1.1 mol) was added to the solution. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 10:1 to 1:1) to afford Intermediate 1 (190 g, 60% yield). |
In diethyl ether at 20℃; | 1.1 Step 1: (3aS,4S,6S)-2-(dichloromethyl)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborole (intermediate 1) To a solution of CH2Cl2 (80 mL, 1.2 mol) in THF (800 mL) at -80° C. to -90° C. was added n-BuLi (2.5 M in hexane, 480 mL, 1.2 mol) under N2 and the reaction mixture was stirred for 1.5 h below -80° C. B(OEt)3 (200 mL, 1.2 mol) was added in one portion and the mixture was stirred for 1 h at -45° C. to -30° C. Aqueous HCl (5 M, 240 mL, 1.2 mol) was then added dropwise at temperature below -20° C. and the resulting mixture was stirred at -20° C. for 4 h. The organic layer was separated, and the water layer was extracted with Et2O (100 mL*2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give an intermediate. The intermediate was re-dissolved in Et2O (800 mL), and pinanediol (188 g, 1.1 mol) was added to the solution. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1~1:1) to afford intermediate 1 (190 g, 60% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | With magnesium sulfate; In diethyl ether; at 20℃; for 3h;Inert atmosphere; | (3-(tert-Butoxycarbonyl)phenyl)boronic acid (978 mg, 4,40 mmol) was suspended in 40 mL Et20 and mixed with (+)-pinanediol (750 mg, 4,40 mmol) and anhydrous MgS04 (1 gram, 8,30 mmol). The mixture was stirred at room temperature under argon for 3 hours before the inorganic material was filtered off and the filtrate concentrated under reduced pressure. This gave a sticky clear oil (1568 mg, 4.40 mmol, >99%) which solidified overnight at room temperature. 1H NMR (600 MHz, Chloroform-d) delta 8.41 (t, J- 1.5 Hz, 1H), 8.07 (dt, J= 7.8, 1.6 Hz, 1H), 7.95 (dt, J= 7.4, 1.4 Hz, 1H), 7.42 (t, J= 7.6 Hz, 1H), 4.47 (dd, J= 8.8, 1.9 Hz, 1H), 2.42 (ddt, J= 14.8, 8.8, 2.4 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.16 (t, J= 5.5 Hz, 1H), 2.05 - 1.89 (m, 2H), 1.60 (s, 10H), 1.49 (s, 3H), 1.31 (s, 3H), 1.19 (s, 1H), 0.89 (s, 3H). 13C NMR (151 MHz, CDC13) delta 166.04, 138.84, 135.78, 132.22, 131.60, 127.79, 86.62, 81.12, 78.57, 77.37, 77.16, 76.95, 66.00, 51.53, 39.67, 38.35, 35.64, 28.84, 28.37, 27.25, 26.65, 24.20, 15.43. MS (ESI positive mode): m/z 379.2 (M+Na+) |
85% | In tetrahydrofuran; at 20℃; for 0.5h; | A solution of (+)- pinanediol (10.0 g, 58.7 mmole) and 3-tert-Butoxycarbonylphenylboronic acid (13.0 g, 58.7 mmole) in tetrahydrofuran (THF, 78 ml_) was stirred for 30 min at room temperature. The solution was concentrated in vacuo, and the residue chromatographed on SiO2 using a gradient of 20% dichloromethane (DCM) in hexane to 70% DCM/hexane to afford 17.76 g (85%) of the product as a slowly crystallizing white solid. Electrospray Ionization Mass Spectrum (ESI-MS) m/z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: allenylmagnesium bromide With Trimethyl borate In diethyl ether at -78 - 0℃; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; water for 1h; Inert atmosphere; Stage #3: pinanediol With magnesium sulfate In diethyl ether at 20℃; for 42h; Inert atmosphere; | 5.2. Procedure for the preparation of the allenyl boronic esters (6, 20, and ent-39) General procedure: Freshly distilled trimethyl borate (21.7 mL, 196 mmol) was added to a round bottom flask containing 150 mL of ether placed in a -78 °C cold bath. A 0 °C solution of allenylmagnesium bromide (1 M in ether, 196 mmol) was added via syringe or cannula at a rate as to keep the internal reaction temperature below -65 °C. A white precipitate formed during this addition. The reaction mixture was stirred 3 h at -78 °C, then was warmed to 0 °C over 1 h and stirred at 0 °C for an additional hour. Aqueous HCl (2 M, 392 mmol) was added via an addition funnel. This mixture was stirred for 1 h and then the organic layer was separated using a separatory funnel. The aqueous layer was washed with ether (2×200 mL) and the combined organic phases were dried over Na2SO4 for 30 min. The solution was filtered under nitrogen and solvent removed in vacuo until 250 mL of solvent remained (the rotary evaporator was flushed and backfilled using an argon balloon). The appropriate diol (137 mmol) was added to the flask and reaction stirred for 24 h at room temperature, at which time 10 g of MgSO4 was added and the mixture stirred for an additional 18 h at room temperature. The reaction was filtered under nitrogen using a coarse fritted funnel and solvent removed in vacuo using argon to backfill the rotary evaporator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | In tetrahydrofuran at 20℃; for 16h; | 1.2 To a solution of tert-butyl 3-(tert-butyldimethylsilyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentanoate XXXVIII (5.4 g, 13 mmol) in THF (25 mL) was added (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (2.4 g, 14.3 mol) at room temperature. The reaction mixture was stirred for 16 h and then was concentrated under vacuum. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) on silica gel to give 1-(tert-butoxy)-3-[(tert-butyldimethylsilyl)oxy]-1-oxo-6-[(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hexan-3-yl XXXIX (5.5 g, 11 mmol, 84.6% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.9% | In tetrahydrofuran at 20℃; for 16h; | 4.1 To a stirred solution of tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2-oxaborinin-6-yl)acetate XLVII (770 mg, 4.58 mmol) in THF (25 mL) was added (1S,2S,3R,55)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (980 mg, 4.58 mmol) at room temperature. The reaction mixture was stirred for 16 h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) on silica gel to give tert-butyl (4Z)-3-hydroxy-6-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hex-4-enoate LIV (1 g, 2.75 mmol, 59.9% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.9% | In tetrahydrofuran at 20℃; for 12h; | 3.3 To a solution of tert-butyl 2-(2-hydroxy-1,2-oxaborinan-6-yl)acetate XLVIII (641 mg, 3.00 mmol) in THF (20 mL) was added (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (509 mg, 3 mol) at room temperature. The reaction mixture was stirred for 16 h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) on silica gel to give tert-butyl 3-hydroxy-6-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hexanoate XLIX (790 mg, 2.16 mmol, 71.9% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | With pyridine; sodium hydrogen sulfate; osmium(VIII) oxide In water | P.38 (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol Preparation Example 38 (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol Me3NO.2H2O (11.3 g, 102 mmol) was dissolved with 16 ml of water, α-pinene (13.2 g, 96.9 mmol), 74 ml of tert-butyl alcohol, 7.4 ml of pyridine and osmium tetroxide (60 mg, 0.236 mmol) were added under stirring. Then nitrogen gas was purged, 10 min later, the reaction mixture was heated to reflux. The reaction was monitored by TLC and finished after 15 h. Spontaneously cooled down to room temperature, NaHSO3 (1.2 g, 11.5 mmol) and an appropriate amount of saturated aqueous NaCl solution were added. The organic phase was separated out, and the water layer was extracted with diethyl ether (3*20 ml), the organic phase was combined and dried over anhydrous sodium sulfate. The product was concentrated and the residue was purified by column chromatography (ethyl acetate:petroleum ether=1:30), 15.33 g of white solid was obtained, and the yield was 92.9%, [α]D20=-10.79° (c=5.5, toluene), m.p.: 52-54° C. 1H-NMR (CDCl3, 300 MHz): δ 0.94 (-CH3, s, 3H), 1.28 (-CH3, s, 3H), 1.32 (-CH3, s, 3H), 1.34~1.38 (-CH2, d, 1H), 1.66 (-CH2, m, 1H), 1.93 (-CH, m, 1H), 2.01 (-CH2, t, 1H), 2.20 (-CH, m, 1H), 2.33 (H2O, s, 2H), 2.49 (-CH2, m, 1H), 4.00 (-CH, q, 1H); 13C-NMR (CDCl3, 300 MHz): δ 24.11, 27.80, 28.00, 29.54, 38.21, 38.99, 40.51, 53.98, 69.26, 73.88; Elemental analysis: C10H18O2, Calculated values C, 70.55; H, 10.66; Measured values C, 70.55; H, 10.67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | (+)-Pinanediol 3-(teri-butoxycarbonyl)benzeneboronate (12b). A solution of tert- butyl 3-bromo-benzoate (1.70 g, 6.61 mmol), obtained from 3-bromobenzoic acid, (Wright, S. W. et al, Tetrahedron Lett. 1997, 38, 7345-7348) and freshly distilled triisopropyl borate (1.53 mL, 6.61 mmol) in THF (17 mL) was cooled to -100 °C under argon flow and w-butyllithium (2.5 M soln in hexane, 2.91 mL, 7.27 mmol) was added dropwise over 15 min, during which the solution turned cherry red. After 1 h at -100 °C, trimethylsilyl chloride (0.84 mL, 6.61 mmol) was dropped into the reactor and the resulting colorless solution was allowed to warm to room temperature and stirred overnight. Finally, (+)-pinanediol (1.12 g, 6.61 mmol) was added and the solution stirred 1 h at room temperature. The mixture was partitioned between ethyl acetate (100 mL) and water (40 mL) and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (light petroleum/ethyl ether 95:5), affording 12b as a yellowish solid (2.10 g, 89percent yield). Mp 70-71 °C. [CC]D +7.3 (c 1.1, CHCI3). XH-NMR (400 MHz, CDC13): delta 0.94 (3H, s, pinanyl CH»), 1.24 (1H, d, J 10.9, pinanyl Hendo), 1.36 (3H, s, pinanyl G¾), 1.53 (3H, s, pinanyl CH3), 1.64 (9H, s, f-Bu), 1.98-2.30 (5H, m, pinanyl protons), 4.51 (1H, dd, J 8.5, 2.0, CHOB), 7.46 (1Eta, t, J7.6, ¾), 8.0 (1Eta, d, J 7.6, H4), 8.12 (1H, d, J7.6, H6), 8.45 (1H, s, H2). 13C-NMR (100 MHz, CDCI3): delta 24.0, 26.5, 27.1, 28.2, 28.7, 35.5, 38.2, 39.5, 51.4, 78.4, 80.9, 86.5, 127.6, 131.5, 132.1, 135.7, 138.7, 169.5, CB not seen. EI-MS: m/z 356 (M+, 10percent), 300 (36), 283 (41), 231 (50), 204 (38), 83 (65), 67 (59), 57 (100). Anal. Calcd. for C2iH29B04: C, 70.80; H, 8.20. Found: C, 70.55; H, 8.22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In tetrahydrofuran for 0.5h; | 4.2 General procedure for the synthesis of (+)-pinanediol boronate General procedure: A solution of the starting boronic acid (3.00 mmol) and (+)-pinanediol (3.00 mmol) in THF (6mL) was stirred for 30min and then concentrated in vacuo. The crude was purified by chromatography (light petroleum/ diethyl ether 7:3), affording the expected compounds with good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In tetrahydrofuran for 0.5h; | 4.2 General procedure for the synthesis of (+)-pinanediol boronate General procedure: A solution of the starting boronic acid (3.00 mmol) and (+)-pinanediol (3.00 mmol) in THF (6mL) was stirred for 30min and then concentrated in vacuo. The crude was purified by chromatography (light petroleum/ diethyl ether 7:3), affording the expected compounds with good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In tetrahydrofuran for 0.5h; | 4.2 General procedure for the synthesis of (+)-pinanediol boronate General procedure: A solution of the starting boronic acid (3.00 mmol) and (+)-pinanediol (3.00 mmol) in THF (6mL) was stirred for 30min and then concentrated in vacuo. The crude was purified by chromatography (light petroleum/ diethyl ether 7:3), affording the expected compounds with good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In diethyl ether at 20℃; for 12h; | 1a.4 Step 4: 2-(3-ethylbenzyl)boronic acid (+)-pinanediol ester A solution of 2-(3-ethylbenzyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (8.7 g, 28.0 mmol) in diethyl ether (90 ml) was treated with (1S, 2S, 3R, 5S)-(+)-pinanediol (7.2 g, 42.0 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 3% of ethyl acetate in petroleum ether, to afford the title compound (9.4 g, colourless liquid, 88%). 1H NMR (400 MHz, CDCI3): δ 7.19-7.16 (m, 1H), 7.04-6.97 (m, 3H), 4.29 (dd, J = 1.88, 8.74 Hz, 1H), 2.65-2.59 (m, 2H), 2.35-2.31 (m, 3H), 2.21-2.17 (m, 1 H), 2.06 (t, J = 5.84 Hz, 1H), 1.90-1.82 (m, 2H), 1.40 (s, 3H), 1.29 (s, 3H), 1.10-1.07 (m, 1H), 0.84 (s, 3H). GCMS: m/z: 298.1. |
88% | In diethyl ether at 20℃; for 12h; | Step 4: 2-(3-ethylbenzyl)boronic acid (+)-pinanediol ester Step 4: 2-(3-ethylbenzyl)boronic acid (+)-pinanediol ester A solution of 2-(3-ethylbenzyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (8.7 g, 28.0 mmol) in diethyl ether (90 ml) was treated with (1 S, 2S, 3R, 5S)-(+)-pinanediol (7.2 g, 42.0 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 3% of ethyl acetate in petroleum ether, to afford the title compound (9.4 g, colourless liquid, 88%). 1H NMR (400 MHz, CDCI3): δ 7.19-7.16 (m, 1 H), 7.04-6.97 (m, 3H), 4.29 (dd, J = 1.88, 8.74 Hz, 1 H), 2.65-2.59 (m, 2H), 2.35-2.31 (m, 3H), 2.21-2.17 (m, 1 H), 2.06 (t, J = 5.84 Hz, 1H), 1.90-1.82 (m, 2H), 1.40 (s, 3H), 1.29 (s, 3H), 1.10-1.07 (m, 1 H), 0.84 (s, 3H). GCMS: m/z: 298.1 |
84% | In diethyl ether at 20℃; for 12h; | 2.4 Step 4: (3-ethylbenzyl)boronic acid (+)-pinanediol ester A solution of 2-(3-ethylbenzyl)-4 ,4,5, 5-tetramethyl-1 ,3,2-dioxaborolane (1.4 g, 5.68 mmol) in diethyl ether (30 ml) was treated with (1 S, 2S, 3R, 5S)-(+)-pinanediol (1 .45 g, 8.53 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether, to afford the title compound (1 .43 g, 84%). 1H NMR (400 MHz, CDCI3) δ 7.19-7.15 (m, 1 H), 7.04-7.01 (m, 2H), 6.98-6.96 (m, 1 H), 4.29-4.27 (m, 1 H), 2.64-2.58 (m, 2H), 2.34-2.28 (m, 3H), 2.20-2.19 (m, 1 H), 2.07-2.04 (m, 1 H), 1.89-1 .81 (m, 2H), 1 .29 (s, 3H), 1 .25-1.21 (m, 3H), 1.1 -1.08 (m, 1 H), 0.84 (s, 3H). GCMS: m/z: 298 |
63% | In diethyl ether at 20℃; | 30 A solution of 2-(3-ethylbenzyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4 g, 16 mmol) in diethyl ether (30 mL) was treated with (lS,2S,3R,5S)-2,6,6-trimethylbicyclo[3. l.l]heptane-2,3- diol (3.5 g, 20.8 mmol). The mixture was stirred at rt for 12 h. Then the mixture was concentrated and the crude was purified by column chromatography on silica gel, eluting with 5% of EtOAc in petroleum ether to afford (3aS,4S,6S,7aR)-2-(3-ethylbenzyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[d] [l,3,2]dioxaborole (3 g, 63%) as a yellow oil. |
In tert-butyl methyl ether at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In diethyl ether; at 20℃; for 12h; | A solution of 2-(3-trifluoromethylbenzyl)-4,4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (5.10 g, 17.8 mmol) in diethyl ether (50 ml) was treated with (1 S, 2S, 3R, 5S)-(+)-pinanediol (4.55 g, 26.7 mmol). The reaction mixture was stirred at room temperature for 12 h, then the mixture was washed with water twice, then with brine and dried over sodium sulphate, then concentrated. The crude product was purified by column chromatography on silica gel, eluting with 2% of ethyl acetate in petroleum ether to afford the title compound (6.0 g, 99%) as a colourless liquid. 1H NMR (400 MHz, CDCI3): delta 7.40 (s, 1 H), 7.35-7.38 (m, 3H), 4.29 (dd, J= 2.0, 8.8 Hz, 1 H), 2.40 (s, 2H), 2.31 -2.36 (m, 1 H), 2.17-2.21 (m, 1 H), 2.05 (t, J= 5.8 Hz, 1 H), 1 .90-1.92 (m, 1 H), 1.80-1 .85 (m, 1 H), 1 .39 (s, 3H), 1 .29 (s, 3H), 1.02-1.05 (m, 1 H), 0.84 (s, 3H). GCMS: m/z=338 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In diethyl ether at 20℃; for 48h; | 1.3 Step 3: (3-thienylmethyl)boronic acid (+)-pinanediol ester A solution of 4,4,5,5-tetramethyl-2-(3-thienylmethyl)-1 ,3,2-dioxaborolane (3.55 g, 15.8 mmol) in diethyl ether (40 ml) was treated with (1 S, 2S, 3R, 5S)-(+)-pinanediol (3.1 g, 18 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mass was washed with water (2 x 15 ml), brine and dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether, to afford the title compound (4.0 g, 90%) 1H NMR (400 MHz, CDCI3) δ 7.23 (dd, J= 7.8, 3.2 Hz, 1 H), 6.97-6.95 (m, 2H), 4.31 (dd, J= 8.8, 2.0 Hz, 1 H), 2.36-2.30 (m, 3H), 2.2-2.18 (m, 1 H), 2.07 (t, J= 5.2Hz, 1 H), 1.92-1.90 (m, 1 H), 1.87-1 .84 (m, 1 H) 1.40 (s, 3H), 1.32 (s, 3H), 1.10 (d, J= 10.9 Hz, 1 H), 0.84 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In diethyl ether at 20℃; | 6.7 Step 7: Synthesis of 1-(3'-benzofuran)methylboronic acid-(1S,2S,3R,5S)-(+)-2,3-decanediol ester (E-8) Compound E-7 (2 g, 7.74 mmol) was dissolved in diethyl ether (25 mL) and (1S,2S,3R,5S)-(+)-2,3-decanediol (1.45 g, 8.51 mmol) After that, it was reacted overnight at room temperature. The reaction mixture was washed twice with water and then brine, dried over anhydrous sodium sulfateThe product was obtained as a colorless oil, 2.11 g, yield 88% |
82% | In diethyl ether at 20℃; for 12h; | 18.4 Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester A solution of 2-(benzofuran-3-ylmethyl)-4,4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (6.1 g, 23.6 mmol) in diethyl ether (60 ml) was treated with (1 S, 2S, 3R, 5S)-(+)-pinanediol (6.0 g, 35.4 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether, to afford the title compound (6.3 g, 82%). 1H NMR (400 MHz, CDCI3): δ 7.56-7.58 (m, 1 H), 7.53-7.55 (m, 1 H), 7.44-7.46 (m, 1 H), 7.23-7.28 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1 H), 2.32-2.34 (m, 1 H), 2.28 (s, 2H), 2.21 - 2.22 (m, 1 H), 2.08 (t, J = 5.88 Hz, 1 H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J = 10.92 Hz, 1 H), 0.85 (s, 3H). GCMS: m/z: 310 |
82% | In diethyl ether at 20℃; for 12h; | 4 Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester A solution of 2-(benzofuran-3-ylmethyl)-4,4,5, 5-tetramethyl-1 , 3,2-dioxaborolane (6.1 g, 23.6 mmol) in diethyl ether (60 ml) was treated with (iS, 2S, 3R, 5S)-(+)- pinanediol (6.0 g, 35.4 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then withbrine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether, to afford the title compound (6.3 g, 82%). 1H NMR (400 MHz, CDCI3): 67.58-7.56 (m, IH), 7.55-7.53 (m, 1H), 7.46-7.44 (m,1H), 7.28-7.23 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1H), 2.34-2.32 (m, 1H), 2.28 (s, 2H), 2.22-2.21 (m, IH), 2.08 (t, J = 5.88 Hz, 1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J= 10.92 Hz, 1H), 0.85 (s, 3H). GCMS: m/z: 310. |
82% | In diethyl ether at 20℃; for 12h; | 1a.4 Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester A solution of 2-(benzofuran-3-ylmethyl)-4,4l5,5-tetramethyl-1,3>2-dioxaborolane (6.1 g, 23.6 mmol) in diethyl ether (60 ml) was treated with (1S, 2S, 3R, 5S)-(+)-pinanediol (6.0 g, 35.4 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether, to afford the title compound (6.3 g, 82%). 1H NMR (400 MHz, CDC ): δ 7.58-7.56 (m, 1 H), 7.55-7.53 (m, 1 H), 7.46-7.44 (m, 1H), 7.28-7.23 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1 H), 2.34-2.32 (m, 1 H), 2.28 (s, 2H), 2.22- 2.21 (m, 1H), 2.08 (t, J = 5.88 Hz, 1 H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J = 10.92 Hz, 1H), 0.85 (s, 3H). GCMS: m/z: 310. |
82% | In diethyl ether at 20℃; for 12h; | 2.4 Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester A solution of 2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (6.1 g, 23.6 mmol) in diethyl ether (60 ml) was treated with (1S, 2S, 3R, 5S)-(+)-pinanediol (6.0 g, 35.4 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether, to afford the title compound (6.3 g, 82%). 1H NMR (400 MHz, CDCI3): δ 7.58-7.56 (m, 1 H), 7.55-7.53 (m, 1 H), 7.46-7.44 (m, 1 H), 7.28-7.23 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1 H), 2.34-2.32 (m, 1H), 2.28 (s, 2H), 2.22- 2.21 (m, 1H), 2.08 (t, J = 5.88 Hz, 1 H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J = 10.92 Hz, 1 H), 0.85 (s, 3H). GCMS: m/z: 310. |
82% | In diethyl ether at 20℃; for 12h; | 4 Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester A solution of 2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (6.1 g, 23.6 mmol) in diethyl ether (60 ml) is treated with (1 S, 2S, 3R, 5S)-(+)-pinanediol (6.0 g, 35.4 mmol). The reaction mixture is stirred at room temperature for 12 h then the mixture is washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product is purified by flash column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether, to afford the title compound (6.3 g, 82%). 1H NMR (400 MHz, CDCI3): δ 7.58-7.56 (m, 1 H), 7.55-7.53 (m, 1 H), 7.46- 7.44 (m, 1 H), 7.28-7.23 (m, 2H), 4.33 (dd, J = 1 .88, 8.76 Hz, 1 H), 2.34-2.32 (m, 1 H), 2.28 (s, 2H), 2.22-2.21 (m, 1 H), 2.08 (t, J = 5.88 Hz, 1 H), 1 .42 (s, 3H), 1 .29 (s, 3H), 1 .13 (d, J = 10.92 Hz, 1 H), 0.85 (s, 3H). GCMS: m/z: 310. |
82% | In diethyl ether at 20℃; for 12h; | 1.4 Step 4: 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester. A solution of 2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (6.1 g, 23.6 mmol) in diethyl ether (60 ml_) is treated with (1S,2S,3R,5S)-(+)-pinanediol (6.0 g, 35.4 mmol). The reaction mixture is stirred at room temperature for 12 h then the mixture is washed with water (twice), then with brine and resulting solution is dried over anhydrous sodium sulphate and concentrated. The crude product is purified by flash column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether to obtain 2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester (6.3 g, 82%). 1H NMR (400 MHz, CDCIs): d 7.58-7.56 (m, 1H), 7.55-7.53 (m, 1H), 7.46-7.44 (m, 1H), 7.28-7.23 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1H), 2.34-2.32 (m, 1H), 2.28 (s, 2H), 2.22-2.21 (m, 1H), 2.08 (t, J = 5.88 Hz, 1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J = 10.92 Hz, 1H), 0.85 (s, 3H). GCMS: m/z: 310. |
82% | In diethyl ether at 20℃; for 12h; Inert atmosphere; | |
80% | In diethyl ether at 20℃; | 31; 41; 47 A solution of 2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.58 g, 17.7 mmol) in diethyl ether (30 mL) was treated with (lS,2S,3R,5S)-2,6,6- trimethylbicyclo[3.l.l]heptane-2,3-diol (3.9 g, 23.1 mmol), the mixture was stirred at rt for 12 h. Then the mixture was concentrated and the crude was purified by column chromatography on silica gel, eluting with 5% of ethylacetate in petroleum ether to afford (3aS,4S,6S,7aR)-2-(benzofuran-3-ylmethyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborole (4.5 g, 80%) as a yellow oil. |
34% | In diethyl ether at 20℃; | 16.4 Into a 50-mL round-bottom flask, was placed a solution of 2-(I -benzofuran-3- ylmethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (490 mg, 1.90 mmol, 1.00 eq.) in ether (5 mL), and ( lS,2S,3R,5S)-2,6,6-tiimethylbicyclo[3.1.1]heptane-2,3~diol (420 mg, 2.47 mmol, 1.30 eq.). The resulting solution was stirred overnight at rt. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (3:97). This resulted in 200 mg (34%) of (lS,2S,6R,8S)-4-( l-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0A[2,6]]decane as a yellow oil. |
In diethyl ether at 20℃; Inert atmosphere; | ||
10.5 g | In diethyl ether at 20℃; | 1.D Step D: Benzofuran-3-ylmethylboronic acid (1S,2S,3R,5S)-(+)-pinane-2,3-diol ester Pinacol benzofuran-3-ylmethylboronic acid (14.0g)And (1S, 2S, 3R, 5S)-(+)-Pinane-2,3-diol (18.4g) were added to anhydrous ether (200mL),The suspension was stirred overnight at room temperature,After the detection reaction is completed, wash with water three times, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent after filtration, and purify the residue by silica gel column chromatography (50% dichloromethane/petroleum ether) to obtain the product (10.5 g). |
10.5 g | In diethyl ether at 20℃; | 1.D Step D: Benzofuran-3-ylmethylboronic acid-(1S,2S,3R,5S)-(+)-pinene-2,3-diol ester Pinacol benzofuran-3-ylmethylboronic acid (14.0g)And (1S, 2S, 3R, 5S)-(+)-Pinane-2,3-diol (18.4g) were added to anhydrous ether (200mL),The suspension was stirred overnight at room temperature. After the LC/MS detection of the reaction was completed,Wash three times with water, dry the organic phase with anhydrous sodium sulfate,After filtration, the solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (50% dichloromethane/petroleum ether) to obtain the product (10.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | In tetrahydrofuran at 20℃; for 16h; | 1.2 [0162] To a solution of tert-butyl 3-(tert-butyldimethylsilyloxy)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pentanoate XXXVIII (5.4 g, 13 mmol) in THF (25 mL) was added (1 S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (2.4 g, 14.3 mol) at room temperature. The reaction mixture was stirred for 16 h and then was concentrated under vacuum. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) on silica gel to give l-(tert-butoxy)-3-[(tert-butyldimethylsilyl)oxy]-l-oxo-6- [(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo [6.1.1.02,6]decan-4-yl]hexan-3-yl XXXIX (5.5 g, 11 mmol, 84.6% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.9% | In tetrahydrofuran at 20℃; for 16h; | 4.1 [0225j To a stirred solution of tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2- oxaborinin-6-yl)acetate XLVII (770 mg, 4.58 mmol) in THF (25 mL) was added (1 S,25,3R,55)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (980 mg, 4.58 mmol) at room temperature. The reaction mixture was stirred for 16 h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane-*30% EtOAc/hexane) on silica gel to give tert-butyl (4Z)-3 -hydroxy-6- [(1 R,2R,65 , 8R)-6,9,9- trimethyl-3 ,5 -dioxa-4- boratricyclo[6.1.1.02,6]decan-4-yl]hex-4-enoate LIV (1 g, 2.75 mmol, 59.9% yield). |
59.9% | In tetrahydrofuran at 20℃; for 16h; | 2-[(3R)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-4,7-dihydro-3H-oxaborepin-7-yl]acetic acid (15) tert-Butyl (Z)-3-[tert-butyl(dimethyl)silyl]oxy-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hex-4-enoate (10). To a stirred solution of compound 2 (770mg, 4.58mmol) in THF (25mL) was added (+)-pinanediol (980mg, 4.58mmol) at room temperature. The reaction mixture was stirred for 16h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) on silica gel to give compound 10 (1g, 2.75mmol, 59.9% yield). |
59.9% | In tetrahydrofuran at 20℃; for 16h; | 2-[(3R)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-4,7-dihydro-3H-oxaborepin-7-yl]acetic acid (15) tert-Butyl (Z)-3-[tert-butyl(dimethyl)silyl]oxy-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hex-4-enoate (10). To a stirred solution of compound 2 (770mg, 4.58mmol) in THF (25mL) was added (+)-pinanediol (980mg, 4.58mmol) at room temperature. The reaction mixture was stirred for 16h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) on silica gel to give compound 10 (1g, 2.75mmol, 59.9% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.9% | In tetrahydrofuran at 20℃; for 16h; | 3.3 Step 3 [0218] To a solution of tert-butyl 2-(2-hydroxy-l,2-oxaborinan-6-yl)acetate XL VIII (641 mg, 3.00 mmol) in THF (20 mL) was added (1 S,2S,3R,5S)-2,6,6- trimethylbicyclo[3.1.1]heptane-2,3-diol (509 mg, 3 mol) at room temperature. The reaction mixture was stirred for 16 h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) on silica gel to give tert-butyl 3- hydroxy-6-[(lR,2R,6S,8R)-6,9,9- trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.02'6]decan-4- yl]hexanoate XLIX (790 mg, 2.16 mmol, 71.9% yield). |
71.9% | In tetrahydrofuran at 20℃; for 16h; | tert-Butyl 3-hydroxy-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hexanoate (4). To a solution of tert-butyl 2-(2-hydroxyoxaborinan-6-yl)acetate 3 (641mg, 3.00mmol) in THF (20mL) was added (+)-pinanediol (509mg, 3mol) at room temperature. The reaction mixture was stirred for 16h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) on silica gel to give compound 4 (790mg, 2.16mmol, 71.9% yield). |
71.9% | In tetrahydrofuran at 20℃; for 16h; | tert-Butyl 3-hydroxy-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hexanoate (4). To a solution of tert-butyl 2-(2-hydroxyoxaborinan-6-yl)acetate 3 (641mg, 3.00mmol) in THF (20mL) was added (+)-pinanediol (509mg, 3mol) at room temperature. The reaction mixture was stirred for 16h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) on silica gel to give compound 4 (790mg, 2.16mmol, 71.9% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran at 20℃; for 91h; | 1.1 Synthesis of 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl)benzoic acid A solution of 3-borono-2-methoxybenzoic acid (Combi-Blocks, 7.42 g, 37.9 mmol) and (+)-pinanediol (6.44 g, 37.8 mmol) in tetrahydrofuran (THF, 56 mL) was stirred at room temperature for 91 h. The solution was concentrated in vacuo and triturated twice with hexanes to afford 12.50 g (-100%) of product as a white solid. ESI-MS m/z 331 (MH)+ |
In toluene for 3h; | 48.1.1a Step la: Synthesis of 3-carboxy-2-methoxy-phenyl boronic acid (+) pinandiolato diester Step la: Synthesis of 3-carboxy-2-methoxy-phenyl boronic acid (+) pinandiolato diester. [00305] To a mixture of 3-carboxy-2-methoxy-phenyl boronic acid (35. Og, 178.5 mmol,) and (+) pinanediol (30.35g, 178.5 mmol) was added toluene (400mL). The resulting mixture was stirred for 3 hr then concentrated under vacuum (28 mmHg, bath temperature 40°C). The resulting solid was dried by toluene azeotrope (2 times, approximately lOOmL). This residue was dried under high vacuum (approx. 1 mmHg) at room temperature for 17.5 hr to give the crude title compound which can be used without further purification. 48.06g of this crude product was recrystallized from 150 mL of chloroform/hexane (1 :5 v/v) to give the pure title compound. The mother liquor from the crystallization was concentrated and purified by silica chromatography (120g silica eluted with 40-100% ethyl acetate in hexane) to give an additional batch of the title compound. | |
In n-heptane Reflux; | 1.4 Step 4: Pinanediol ester formation [00185] The pinanediol ester formation was performed in the same reactor used for isolation of intermediate 3 without cleaning. The intermediate 3 sticking to walls of the reactor in the reaction (estimated up to 3 kg; 15.3 mol). Additionally, 36.5 kg damp intermediate 3 (approx. 29.6 kg pure intermediate, 151.0 mol) and 30.0 kg (+)-pinanediol (176.2 mol, 1.1 eq) were charged. Solids were suspended in n-heptane (290 kg), the mixture was heated to reflux and water was removed by distillation. After stirring overnight, there was remaining intermediate 3 on the walls of the reactor. Additional n-heptane (210 kg) was added to increase the filling level and refluxing was continued at reduced pressure. However, there was still remaining intermediate 3, which was not taken up in n-heptane. A sample taken after crystallization showed no remaining intermediate 3. Q-NMR of the mother liquor (approx. 500 kg) showed an excess of approx. 3.8 kg unreacted pinanediol and 4.3 kg product. Based on the amount of pinanediol used, 50.9 kg of the desired product 4 was formed. (0271) Accordingly, there was approx. 46.6 kg product suspended. (0272) [00186] The product 4 was filtered and washed with heptane (30 kg). Drying on the filter overnight provided 44.1 kg desired product (LOD: 0.04%, 88% yield based on damp product used). (0273) [00187] After completion, the reactor was cleaned with THF showing approx. 2 kg desired product 4 and a minor amount of intermediate 3 (approx. 0.5 kg) in the wash solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1H-imidazole; iron(III) chloride In water; acetonitrile at 20℃; for 0.5h; Inert atmosphere; | 2.2. General Procedure B : Transformation of Boronic Acids into Boronates General procedure: To a solution of aryl boronic acid (1 mmol) in MeCN (4 mL) was added, sequentially, asolution of FeCl3 (8 mg, 0.05 mmol, 5 mol%) in H2O (1 mL), imidazole (204 mg, 3 mmol)and pinacol (118 mg, 1 mmol). The resulting cloudy orange mixture was stirred at roomtemperature for 30 min. The reaction was then diluted with H2O (5 mL) and extracted withEt2O (3 x 8 mL). The combined organic extracts were dried (Na2SO4) and concentrated invacuo. The resulting oil was then purified by a filtration through a silica gel plug (eluting withEt2O), affording the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1H-imidazole; iron(III) chloride; In water; acetonitrile; at 20℃; for 0.5h;Inert atmosphere; | General procedure: To a solution of aryl boronic acid (1 mmol) in MeCN (4 mL) was added, sequentially, asolution of FeCl3 (8 mg, 0.05 mmol, 5 mol%) in H2O (1 mL), imidazole (204 mg, 3 mmol)and pinacol (118 mg, 1 mmol). The resulting cloudy orange mixture was stirred at roomtemperature for 30 min. The reaction was then diluted with H2O (5 mL) and extracted withEt2O (3 x 8 mL). The combined organic extracts were dried (Na2SO4) and concentrated invacuo. The resulting oil was then purified by a filtration through a silica gel plug (eluting withEt2O), affording the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In tetrahydrofuran at 20℃; | 22.7 Synthesis of compound 22H The solution of compound 22G (720 mg, 1.6 mmol) and (+)-pinanediol (412 mg, 2.4 mmol) in THF (15 mL) was stirred at room temperature for overnight before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes, v/v, 1/40 to 1/20) to give the titled compound 22H (756 mg, 95%) as yellow solid. MS calcd for (C28H39B07): 498 MS (ESI, positive) found: (M+l): 499 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In diethyl ether at 20℃; for 12h; | 2 Step 2: 2-(4-methylbenzyl)boronic acid (+)-pinanediol ester A solution of 4,4,5,5-tetramethyl-2-(4-methylbenzyl)-1 ,3,2-dioxaborolane (9.3g,37.6 mmol) in diethyl ether (90 ml) was treated with (iS, 2S, 3R, 5S)-(+)-pinanediol (9.7 g, 56.4 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with3% of ethyl acetate in petroleum ether, to afford the title compound (11.0 g, colourless liquid, 93%).1H NMR (400 MHz, CDCI3): 6400 MHz, CDCI3: 6 7.08 (s, 4H), 4.28 (dd, J = 1.88,8.74 Hz, 1H), 2.34-2.28 (m, 6H), 2.21-2.17 (m, 1H), 2.06 (t, J = 5.80 Hz, 1H),1.91-1.81 (m, 2H), 1.39 (s, 3H), 1.29 (5, 3H), 1.07-0.91 (m, 1H), 0.84 (s, 3H). GCMS: m/z: 284.3. |
93% | In diethyl ether at 20℃; for 12h; | 2.2 Step 2: 2-(4-methylbenzyl)boronic acid (+)-pinanediol ester Step 2: 2-(4-methylbenzyl)boronic acid (+)-pinanediol ester A solution of 4,4,5,5-tetramethyl-2-(4-methylbenzyl)-1 ,3,2-dioxaborolane (9.3g, 37.6 mmol) in diethyl ether (90 ml) was treated with (1S, 2S, 3R, 5S)-(+)-pinanediol (9.7 g, 56.4 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 3% of ethyl acetate in petroleum ether, to afford the title compound ( 1.0 g, colourless liquid, 93%). 1H NMR (400 MHz, CDCI3): δ 400 MHz, CDCI3: δ 7.08 (s, 4H), 4.28 (dd, J = 1.88, 8.74 Hz, 1 H), 2.34-2.28 (m, 6H), 2.21-2.17 (m, 1 H), 2.06 (t, J = 5.80 Hz, 1 H), 1.91-1.81 (m, 2H), 1.39 (s, 3H), 1.29 (s, 3H), 1.07-0.91 (m, 1H), 0.84 (s, 3H). GCMS: m/z: 284.3. |
93% | In diethyl ether at 20℃; for 12h; | 3.2 Step 2: 2-(4-methylbenzyl)boronic acid (+)-pinanediol ester A solution of 4,4,5,5-tetramethyl-2-(4-methylbenzyl)-1,3,2-dioxaborolane (9.3g, 37.6 mmol) in diethyl ether (90 ml) was treated with (1S, 2S, 3R, 5S)-(+)-pinanediol (9.7 g, 56.4 mmol). The reaction mixture was stirred at room temperature for 12 h then the mixture was washed with water twice, then with brine and dried over anhydrous sodium sulphate, then concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 3% of ethyl acetate in petroleum ether, to afford the title compound (11.0 g, colourless liquid, 93%). 1H NMR (400 MHz, CDCfe): δ 400 MHz, CDCI3 : δ 7.08 (s, 4H), 4.28 (dd, J = 1.88, 8.74 Hz, 1H), 2.34-2.28 (m, 6H), 2.21-2.17 (m, 1 H), 2.06 (t, J = 5.80 Hz, 1 H), 1.91-1.81 (m, 2H), 1.39 (s, 3H), 1.29 (s, 3H), 1.07-0.91 (m, 1H), 0.84 (s, 3H). GCMS: m/z: 284.3 |
In tert-butyl methyl ether at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.7% | In diethyl ether at 20℃; for 14h; Cooling with ice; Inert atmosphere; | 5 Step 5: Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo [6.1.1 .02,6]decane To an ice-cooled solution of 7-Methyl-3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan- 2-ylmethyl)-benzofuran (5.00 g; 18.37 mmol; 1.00 eq.) in Et20 (50.00 ml; 10.00 V) under nitrogen atmosphere was added IS, 2S, 3R, 5S-(+)-2,3-pinane diol (4.69 g;27.56 mmol; 1.50 eq.) and the reaction mixture was stirred at RT for 14 h. TLC analysis showed completion of reaction. The reaction mixture was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude was purified by flash column chromatography using 2 % ethyl acetate in petroleum ether to get (1S,2S,6R,8S)-2,9,9-Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[6. 1.1.02,6] decane (5.00 g; 13.00 mmol;70.7 %; colorless liquid; Purified Product).GCMS: mlz: 324.21H NMR, 400 MHz, CDCI3: 7.53-7.55 (m, 1H), 7.39-7.40 (m, 1H), 7.12-7.27 (m,1H), 7.06-7.08 (m, IH), 4.31-4.34 (m, IH), 2.53 (s, 3H), 2.30-2.37 (m, 1H), 2.26 (s, 2H), 2.18-2.23 (m, IH), 2.07 (t, J = 5.76 Hz, 1H), 1.84-1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.12-1.15 (m, 1H), 0.85 (s, 3H). |
70.7% | In diethyl ether at 20℃; for 14h; Inert atmosphere; Cooling with ice; | 1b.5 Step 5: TrimethyI-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo [6.1.1.02,6]decane Step 5: TrimethyI-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo [6.1.1.02,6]decane To an ice-cooled solution of 7-Methyl-3-(4l4,5>5-tetramethyl-[1,3,2]dioxaborolan-2- ylmethyl)-benzofuran (5.00 g; 18.37 mmol; 1.00 eq.) in Et20 (50.00 ml; 10.00 V) under nitrogen atmosphere was added 1S, 2S, 3R, 5S-(+)-2,3-pinane diol (4.69 g; 27.56 mmol; 1.50 eq.) and the reaction mixture was stirred at RT for 14 h. TLC analysis showed completion of reaction. The reaction mixture was washed with brine. The organic layer was dried over anhydrous Na2S04 and concentrated. The crude was purified by flash column chromatography using 2 % ethyl acetate in petroleum ether to get (1S,2S,6R,8S)-2,9,9-Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo[6.1.1.02,6] decane (5.00 g; 13.00 mmol; 70.7 %; colorless liquid; Purified Product). GCMS: m/z: 324.2 1H NMR, 400 MHz, CDCI3: 7.53-7.55 (m, 1H), 7.39-7.40 (m, 1 H), 7.12-7.27 (m, 1H), 7.06-7.08 (m, 1H), 4.31-4.34 (m, 1 H), 2.53 (s, 3H), 2.30-2.37 (m, 1H), 2.26 (s, 2H), 2.18- 2.23 (m, 1H), 2.07 (t, J = 5.76 Hz, 1H), 1.84-1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.12-1.15 (m, 1 H), 0.85 (s, 3H). |
70.7% | In diethyl ether at 20℃; for 14h; Cooling with ice; Inert atmosphere; | 1b.5 Step 5: Trimethyl-4-(7-methyI-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo [6.1.1.02,6]decane To an ice-cooled solution of 7-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- ylmethyl)-benzofuran (5.00 g; 18.37 mmol; 1.00 eq.) in Et20 (50.00 ml; 10.00 V) under nitrogen atmosphere was added 1S, 2S, 3R, 5S-(+)-2,3-pinane diol (4.69 g; 27.56 mmol; 1.50 eq.) and the reaction mixture was stirred at RT for 14 h. TLC analysis showed completion of reaction. The reaction mixture was washed with brine. The organic layer was dried over anhydrous Na2S04 and concentrated. The crude was purified by flash column chromatography using 2 % ethyl acetate in petroleum ether to get (1S,2S,6R,8S)-2,9l9-Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo[6.1.1.02,6] decane (5.00 g; 13.00 mmol; 70.7 %; colorless liquid; Purified Product). GCMS: m/z: 324.2 1H NMR, 400 MHz, CDCI3: 7.53-7.55 (m, 1 H), 7.39-7.40 (m, 1 H), 7.12-7.27 (m, 1 H), 7.06-7.08 (m, 1 H), 4.31-4.34 (m, 1H), 2.53 (s, 3H), 2.30-2.37 (m, 1 H), 2.26 (s, 2H), 2.18- 2.23 (m, 1 H), 2.07 (t, J = 5.76 Hz, 1H), 1.84-1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.12-1.15 (m, 1H), 0.85 (s, 3H). |
70.7% | In diethyl ether at 20℃; for 14h; Inert atmosphere; Cooling with ice; | Step 5: Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo [6.1.1.02,6]decane Step 5: Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo [6.1.1.02,6]decane To an ice-cooled solution of 7-Methyl-3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- ylmethy -benzofuran (5.00 g; 18.37 mmol; 1.00 eq.) in Et20 (50.00 ml; 10.00 V) under nitrogen atmosphere was added 1 S, 2S, 3R, 5S-(+)-2,3-pinane diol (4.69 g; 27.56 mmol; 1.50 eq.) and the reaction mixture was stirred at RT for 14 h. TLC analysis showed completion of reaction. The reaction mixture was washed with brine. The organic layer was dried over anhydrous a2S04 and concentrated. The crude was purified by flash column chromatography using 2 % ethyl acetate in petroleum ether to get (1S,2S,6R,8S)-2,9,9-Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora- tricyclo[6.1.1.02,6] decane (5.00 g; 13.00 mmol; 70.7 %; colorless liquid; Purified Product). GCMS: m/z: 324.2 1H NMR, 400 MHz, CDCI3: 7.53-7.55 (m, 1 H), 7.39-7.40 (m, 1 H), 7.12-7.27 (m, 1 H), 7.06-7.08 (m, 1 H), 4.31-4.34 (m, 1 H), 2.53 (s, 3H), 2.30-2.37 (m, 1 H), 2.26 (s, 2H), 2.18- 2.23 (m, 1 H), 2.07 (t, J = 5.76 Hz, 1 H), 1.84-1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.12-1.15 (m, 1 H), 0.85 (s, 3H). |
70.7% | In diethyl ether at 20℃; for 14h; Inert atmosphere; Cooling with ice; | 3.5 Step 5: Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane. To an ice-cooled solution of 7-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran (5.00 g; 18.37 mmol; 1.00 eq.) in Et20 (50.00 ml_) under nitrogen atmosphere is added 1S, 2S, 3R, 5S-(+)-2,3-pinane diol (4.69 g; 27.56 mmol; 1.50 eq.) and the reaction mixture is stirred at rt for 14 h. TLC analysis showed completion of reaction. The reaction mixture is washed with brine. The organic layer is dried over anhydrous Na2S04 and concentrated. The crude is purified by flash column chromatography using 2 % ethyl acetate in petroleum ether to get (1S,2S,6R,8S)-2,9,9-Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane (5.00 g; 13.00 mmol; 70.7 %; colorless liquid). GCMS: m/z: 324.2 1H NMR, 400 MHz, CDCI3: 7.53-7.55 (m, 1H), 7.39-7.40 (m, 1H), 7.12-7.27 (m, 1H), 7.06-7.08 (m, 1H), 4.31 -4.34 (m, 1H), 2.53 (s, 3H), 2.30-2.37 (m, 1H), 2.26 (s, 2H), 2.18-2.23 (m, 1H), 2.07 (t, J = 5.76 Hz, 1H), 1.84-1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.12-1.15 (m, 1H), 0.85 (s, 3H). |
In tert-butyl methyl ether at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 1-bromo-4-butene; benzo[1,3,2]dioxaborole at 110℃; for 18h; Inert atmosphere; Stage #2: pinanediol In tetrahydrofuran at 23℃; for 18h; | 1 Step 1: Preparation of (3 aS,4S, 6S,7aR)-2-(4-bromobutyl)-3 a, 5,5 -trimethylhexahydro4,6-methanobenzo[d][1,3,2]dioxaborolej Into a 40 mL vial equipped with a magnetic stir bar and under nitrogenwas added catechol borane (8.79 g, 72 mmol, 1.0 equiv) and 4-bromo-1-butene (10 g, 72mmol, 1.0 equiv). The solution turned slightly cloudy and was heated to 110 °C for 18 hovernight. The contents of the vial were cooled to room temperature and transferred into a 250 mL round-bottom flask using THF (60 mL). To the flask was added (1S,2S,3R,5S’)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (12.5 g, 72 mmol, 1.0 equiv) and the mixture stirred at room temperature for 18 h. The solution was concentrated under reduced pressure and loaded onto a silica gel column (240 g) and eluted with 100:0 to 90:10 Hexanes:EtOAc as a gradient. The product fractions were concentrated under reduced pressure to afford a clear oil (15.8 g, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: allyl bromide; benzo[1,3,2]dioxaborole at 100℃; for 3h; Inert atmosphere; Stage #2: pinanediol In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
57% | Stage #1: allyl bromide; benzo[1,3,2]dioxaborole at 110℃; for 8h; Inert atmosphere; Stage #2: pinanediol In tetrahydrofuran at 23℃; for 18h; | 1 Step 1: Preparation of (3aS,4S,6S,7a]?)-2-(3-bromopropyl)-3a,5,5-trimethylhexahydro-4, 6-methanobenzo[d] [1,3,2] dioxaborole Into a round-bottom flask equipped with a magnetic stir bar and under nitrogen was added catechol borane (6.2 mL, 58 mmol, 1.0 equiv) and ally bromide (5 mL, 58 mmol, 1.0 equiv). The solution was heated to 110 °C for 8 h. The contents of the vial were cooled to room temperature and transferred with THF (100 mL). To the flask was added (1S,2S,3R, 5S)-2,6,6-trimethylbicyclo[3. 1.1 ]heptane-2,3 -diol (9.8 g, 58 mmol, 1.0 equiv) and the mixture stirred at room temperature for 18 h. The solution was concentrated under reduced pressure, loaded onto a silica gel column (220 g) and eluted with 100:0 to 90:10 Hexanes:EtOAc as a gradient. The product fractions were concentrated under reduced pressure to afford a clear oil (9.93 g, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: bromopentene; benzo[1,3,2]dioxaborole at 110℃; for 16h; Inert atmosphere; Stage #2: pinanediol In tetrahydrofuran at 23℃; for 16.3333h; | 63.1 Step 1: Preparation of (3 aS,4S,6S,7aR)-2-(5-bromopentyl)-3 a, 5,5-trimethylhexahydro-4, 6-methanobenzo[d] [1,3,2] dioxaborole General procedure: Into a 40 mL vial equipped with a magnetic stir bar and under nitrogen was combined 5-bromo-1-pentene (10 g, 66 mmol, 1.0 equiv) and catecholborane (8.1 g, 66 mmol, 1.0 equiv). The neat mixture was heated to 110 °C for 16 h. In a separate 250 mL round bottom flask equipped with a magnetic stir bar was added (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (11.4 g, 66 mmol, 1.0 equiv) and THF (60 mL). After the solids had dissolved, the prepared borate was added via syringe over 20 minutes. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography through silica gel, eluting with 100:0 to 90:10 Hexanes:EtOAc as a gradient. The desired product was obtained as a clear oil (6.6 g, 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | In tetrahydrofuran at 20℃; for 18h; | 40 Preparation example 40 dichloromethyl boronic acid-α-pinanediol ester Preparation example 40 dichloromethyl boronic acid-α-pinanediol ester To a 25ml of flask was added the product of α-pinanediol of Preparation example 38 (3.23g, 0.019mmol) and the product of dichloromethyl boronic acid dimethyl ester of Preparation example 39 (5.38g, 0.035mmol), then dissolved with 5ml of THF, stirred at room temperature. The reaction was monitored by TLC and finished after 18h. Separated by column chromatography (ethyl acetate: petroleum ether = 1: 20)to give 4.92g of colorless liquid with a yield of 98.5%. 1H-NMR (CDCl3, 300MHz): δ 0.85 (-CH3, s, 3H), 1.21 (-CH2, t, 1H), 1.31 (-CH3, s, 3H), 1.47 (-CH3, s, 3H), 1.92∼1.97 (-CH2, CH, m, 2H), 2.15 (-CH, t, 1H), 2.25∼2.43 (-CH2, m, 2H), 4.47 (-CH, q, 1H), 5.40 (-CH, s, 1H); 13C-NMR (CDCl3, 75MHz): δ 23.92, 26.18, 26.93, 28.18, 34.98, 38.31, 39.16, 51.09, 79.41, 88.08. MS (EI): m/z 262.0 (M+), Calculated value m/z 262.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | With pyridine; osmium(VIII) oxide; trimethylamine-N-oxide In water; <i>tert</i>-butyl alcohol for 15h; Inert atmosphere; Reflux; | 38 Preparation example 38 (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3 -diol Preparation example 38 (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3 -diol Me3NO·2H2O (11.3g, 102mmol) was dissolved with 16ml of water, α-pinene (13.2g, 96.9mmol), 74ml of tert-butyl alcohol, 7.4ml of pyridine and osmium tetroxide (60mg, 0.236mmol) were added under stirring. Then nitrogen gas was purged, 10 min later, the reaction mixture was heated to reflux. The reaction was monitored by TLC and finished after 15 h. Spontaneously cooled down to room temperature, NaHSO3 (1.2g, 11.5mmol) and an appropriate amount of saturated aqueous NaCl solution were added. The organic phase was separated out, and the water layer was extracted with diethyl ether (3*20ml), the organic phase was combined and dried over anhydrous sodium sulfate. The product was concentrated and the residue was purified by column chromatography (ethyl acetate: petroleum ether= 1: 30), 15.33g of white solid was obtained, and the yield was 92.9%, [α]D20=-10.79° (c=5.5, toluene), m.p.: 52-54°C. 1H-NMR (CDCl3, 300MHz): δ 0.94 (-CH3, s, 3H), 1.28 (-CH3, s, 3H), 1.32 (-CH3, s, 3H), 1.34∼1.38 (-CH2, d, 1H), 1.66 (-CH2, m, 1H), 1.93 (-CH, m, 1H), 2.01 (-CH2, t, 1H), 2.20 (-CH, m, 1H), 2.33 (H2O s, 2H), 2.49 (-CH2, m, 1H), 4.00 (-CH, q, 1H); 13C-NMR (CDCl3, 300MHz): δ 24.11, 27.80, 28.00, 29.54, 38.21, 38.99, 40.51, 53.98, 69.26, 73.88; Elemental analysis: C10H18O2, Calculated values C, 70.55; H, 10.66; Measured values C, 70.55; H, 10.67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.5 g | Stage #1: Triisopropyl borate; Chloroiodomethane With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5h; Stage #2: With chloro-trimethyl-silane In tetrahydrofuran; hexane for 18h; Stage #3: pinanediol In tetrahydrofuran; hexane for 4h; | 1.1.A-2 Step 1A-2: Synthesis of 4-chloromethyl-2,9,9-trimethyl-3,5-dioxa-4-bora- tricycloj6.1.1.02,61 -decane (lAc). To a solution of chloroiodomethane (27.0 mL, 367 mmol) in THE (367 mL) at -78 °C was added triisopropyl borate (78.5 mL, 340 mmol) followed by slowly addition of n-BuLi solution (147 mL, 367 mmol, 2.5 M in hexanes), down the side of the flask over 50 mm, and stirring was continued for additional 40 mm. To the resulted milky mixture was added chlorotrimethylsilane (46.6 mL, 367 mmol) over 5 mm. The cold bath was removed, and stirring continued for 18 hr. To the resulted mixture was added a solution of(1S, 2S, 3R, 5S)-(+)-2,3- pinanediol (57.87 g, 340 mmol) in THF (170 mL) over 5 mm, and stirring continued for 4 hr. The resulted yellow solution was diluted with ether (1.5 L) and washed H20 (400 mL). The organic layer was separated and washed with brine, dried over Na2 SO4, concentrated, and flash chromatographed on a silica gel (1040 g) column, eluted with hexanes/EtOAc (0-4%) to give an oil (69.5 g). The compound was immediately used in next step of reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium permanganate; tetrabutyl-ammonium chloride; potassium hydroxide In dichloromethane at -40 - -15℃; for 10h; Large scale; | 2.1 Example 2 Synthesis of (IS, 2S, 3R, 5S) - (+) _2,3-pinanediol (1) L-pinene 272kg into the 5000L reactor, Under stirring, methylene chloride (800 L) was added, Then add potassium hydroxide 16kg, at -40 ° C to _15 ° C temperature, 4 kg of tetrabutylammonium chloride was added and an aqueous solution of potassium permanganate (320 kg) was added in portions. After l0 h, the solid residue was removed by filtration. The reaction solution was concentrated to remove the solvent and the remaining very small amount of piniophene, (1S, 2S, 3R, 5S) - (+) -2,3-pinanediol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.8 g | With magnesium sulfate In tetrahydrofuran at 20℃; for 12h; | 13.5 Step 5: Synthesis of 12B To a solution of crude compound 13E (~ 45 mmol, 1.0 eq) in THF (~ 150 mL) was added (+)-pinanediol (23.0 g, 135 mmol, 3.0 eq) and MgS04 (20 g). The resulting reaction mixture was stirred at rt for 12 hours before it was filtered and concentrated to dryness. The obtained residue was purified by column chromatography (hexanes/EtOAc= 5/1 to 3/1) to give compound 12B (12.1 g, ~ 90% purity and ~ 93% de) as yellow solid. The product was further purified by re-crystallization in 10% ethyl acetate in hexanes to give 6.8 g pure 12B (> 99% purity and > 99% de). JH NMR(CDC13, 400 MHz) for 12B: δ 7.32-7.25 (m, 1H), 6.72 (t, / = 9.2 Hz, 1H), 4.00 (dd, / = 1.6, 1.6 Hz, 1H), 2.28-2.24 (m, 1H), 2.17-2.14 (m, 1H), 1.86-1.81 (m, 2H), 1.75 (s, 8H), 1.62 (d, / = 1.2 Hz, 1H), 1.21-1.19 (m, 1H), 1.18 (s, 3H), 1.17 (s, 3H), 1.16-1.13 (m, 1H), 0.72 (s, 3H), 0.53-0.47 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In tetrahydrofuran at 20℃; | 20.9 Step 9: Synthesis of compound 20.J A mixture of 201 (4.75 g, 12.0 mmol, 1.0 eq) and (+)-pinanediol (4.08 g, 24.0 mmol, 2.0 eq) in THF (50 mL) was stirred at rt overnight. The reaction was concentrated and purified by flash column chromatography (ethyl acetate : hexane = 1:3 to 1:2) to give compound 20J (4.0 g, 75%) as light yellow oil. |
75% | In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With C21H12Cl6NO4V; oxygen In toluene at 1000℃; for 1.5h; chemoselective reaction; | |
98 %Spectr. | With N-Bromosuccinimide; (oxybis(2,1-phenylene))bis(diphenylbismuthane); potassium carbonate In [D3]acetonitrile at 23℃; for 0.5h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In diethyl ether; at 20℃; | A solution of (l S,2S,3 ,5S)-2,6,6-irimeihylbicyclo[3.1.1]heptane-2,3-diol (4.9 g, 28.8 mmol) in diethyl ether (100 mL) was treated with 2-(4-niethoxybenzyl)-4,4,5,5~tetramethyl-l,3,2- dioxaborolane (5 g, 20 mmol), the mixture was stirred at rt for 12 h. Then the mixture was concentrated and the crude was purified by column chromatography on silica gel, eluting with 5% of ethyl acetate in petroleum ether to afford the (3aS,4S,6S,7aR)-2-(4-methoxybenzyl)-3a,5,5-irimethylhexaliydro-4,6- methanobenzo[d] | 1,3,2 jdioxaborole (4.5 g, 75%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.0326 g | With dmap; triethylamine In dichloromethane at 20℃; Inert atmosphere; | General procedure II: preparation of THENA-d2 ester 8-27. General procedure: Oxalyl chloride and DMF (1-2 drops) were added slowly to THENA-d2 (R)-(-)-2 or (S)-(+)-2 in dry CH2Cl2 under a nitrogen atmosphere at room temperature. The reaction mixture was stirred continuously for 3 h followed by evaporation to dryness under vacuum for 1 h to give the corresponding acid chloride. A solution of the acid chloride in dry CH2Cl2 was transferred to a mixture of the chiral secondary alcohol, triethylamine, and DMAP in dry CH2Cl2, then the resulting solution was stirred overnight. After the reaction was quenched with sat. NaHCO3 solution, the crude reaction mixture was extracted 3 times with CH2Cl2 and the organic layer was collected, dried over anh. Na2SO4, filtered, and evaporated to dryness. The crude product was purified by PLC (silica gel, hexane:EtOAc as eluents) to give the corresponding THENA-d2 ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.0339 g | With dmap; triethylamine In dichloromethane at 20℃; Inert atmosphere; | General procedure II: preparation of THENA-d2 ester 8-27. General procedure: Oxalyl chloride and DMF (1-2 drops) were added slowly to THENA-d2 (R)-(-)-2 or (S)-(+)-2 in dry CH2Cl2 under a nitrogen atmosphere at room temperature. The reaction mixture was stirred continuously for 3 h followed by evaporation to dryness under vacuum for 1 h to give the corresponding acid chloride. A solution of the acid chloride in dry CH2Cl2 was transferred to a mixture of the chiral secondary alcohol, triethylamine, and DMAP in dry CH2Cl2, then the resulting solution was stirred overnight. After the reaction was quenched with sat. NaHCO3 solution, the crude reaction mixture was extracted 3 times with CH2Cl2 and the organic layer was collected, dried over anh. Na2SO4, filtered, and evaporated to dryness. The crude product was purified by PLC (silica gel, hexane:EtOAc as eluents) to give the corresponding THENA-d2 ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran at 20℃; for 15h; | 1.II.2 Step 2. Synthesis of 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxo-4-boro-tricyclic (6,1,1,02, 6) decyl-4-benzoic acid-tert-butyl ester (Compound B-3) (+)-2,3-pinanediol (2.70 g, 15.9 mmol) and tert-butyl 3-dihydroxyboryl-2-methoxybenzoate (compound B-2, 4.0 g, 15.9 mmol) dissolved in tetrahydrofuran (THF, 21 mL) were mixed and stirred at room temperature for 15 h. The solution was concentrated in vacuo and the residue was washed with hexane to obtain 5.0 g (86%) of a slowly crystallized white solid, ESI-MS M/Z 409 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With Echavarren's catalyst In 1,2-dichloro-ethane at 80℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In diethyl ether at 20℃; for 14h; Cooling with ice; Inert atmosphere; | 2 Step 2: (1S,2S,6R,8S)-4-(2,4-Dimethyl-benzyl)-2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.02'6]decane To an ice-cooled solution of 2-(2,4-Dimethyl-benzyl)-4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolane (24.00g; 79.3 mmol; 1 .0 eq.) in Diethyl ether (240.00 ml) under nitrogen atmosphere, (1 S,2S,3R,5S)-2,6,6-Trimethyl- bicyclo[3.1 .1 ]heptane-2,3-diol (20.68g; 1 19.07 mmol; 1 .50 eq.) is added and the reaction mixture is stirred at rt for 14 h. TLC analysis showed completion of reaction. The reaction mixture is washed with brine. The organic layer is dried over anhydrous Na2SO4 and concentrated. The crude is purified by flash column chromatography using 2 % ethyl acetate in petroleum ether to get (1 S,2S,6R,8S)-4-(2,4-Dimethyl-benzyl)-2,9,9-trimethyl-3,5-dioxa-4- bora-thcyclo[6.1 .1 .02'6]decane (28.00g; 82.96 mmol; 90.0 %) as colorless oil. 1H NMR (400 MHz, CDCI3): δ 7.05-7.03 (m, 1 H), 6.95-6.94 (m, 1 H), 6.92- 6.90 (m, 1 H), 4.27-4.25 (m, 1 H), 2.33-2.30 (m, 9H), 2.27-2.17 (m, 1 H), 2.05 (t, J = 5.76 Hz, 1 H), 1 .90-1 .89 (m, 1 H), 1 .84-1 .80 (m, 1 H), 1 .38 (s, 3H), 1 .28 (s, 3H), 1 .1 1 -1 .09 (m, 1 H), 0.91 (s, 3H) GCMS: m/z: 298.3. |
90% | In diethyl ether at 20℃; for 14h; Inert atmosphere; Cooling with ice; | 2.2 Step 2: (1S,2S,6R,8S)-4-(2,4-Dimethyl-benzyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane. To an ice-cooled solution of 2-(2,4-Dimethyl-benzyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (24.00g; 79.3 mmol; 1.0 eq.) in diethyl ether (240.00 ml_) under nitrogen atmosphere, (1S,2S,3R,5S)-2,6,6-Trimethyl-bicyclo[3.1.1]heptane-2,3-diol (20.68g; 1 19.07 mmol; 1.50 eq.) is added and the reaction mixture is stirred at rt for 14 h. TLC analysis shows completion of reaction. The reaction mixture is washed with brine. The organic layer is dried over anhydrous Na2S04 and concentrated. The crude is purified by flash column chromatography using 2 % ethyl acetate in petroleum ether to obtain (1S,2S,6R,8S)-4-(2,4-Dimethyl-benzyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]decane (28.00g; 82.96 mmol; 90.0 %) as colorless oil. 1H NMR (400 MHz, CDCIs): d 7.05-7.03 (m, 1H), 6.95-6.94 (m, 1H), 6.92-6.90 (m, 1H), 4.27-4.25 (m, 1H), 2.33-2.30 (m, 9H), 2.27-2.17 (m, 1H), 2.05 (t, J = 5.76 Hz, 1H), 1.90-1.89 (m, 1H), 1.84-1.80 (m, 1H), 1.38 (s, 3H), 1.28 (s, 3H), 1.1 1 -1.09 (m, 1H), 0.91 (s, 3H) GCMS: m/z: 298.3. |
In tert-butyl methyl ether at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With magnesium sulfate In toluene at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In diethyl ether at 20℃; | 66 Into a 250-mL round-bottom flask, was placed 4,4,5,5-tetramethyl-2-[[4-(trifluoro methyl)phenyl] methyl] -1,3, 2-dioxaborolane (2.36 g, 8.25 mmol, 1 eq.), Et20 (30 mL), and (1S,2S,3R,5S)- 2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (2.8 g, 16.5 mmol, 2 eq.). The resulting solution was stirred for 16 h at rt. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate :petroleum ether (0: 100-3:97). This resulted in 2.2 g (79%) of (lS,2S,6R,8S)-2,9,9- trimethyl-4-[[4-(trifluoromethyl)phenyl]methyl]-3,5-dioxa-4-boratricyclo[6.1.1.0A[2,6]]decane as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In diethyl ether; at 20℃; for 16h;Inert atmosphere; | In a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[(4-fluorophenyl)methyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (15.3 g, 64.8 mmol, 1 eq.), (lS,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (14.3 g, 84 mmol, 1.3 eq.) and ethoxyethane (153 mL). The resulting solution was stirred 16 h at rt. The resulting mixture was washed with brine (160 mL). The aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash silica gel column with pure petroleum ether increasing to ethyl acetate:petroleum ether (1:3). This resulted in 16.7 g (89%) of (lS,2S,6R,8S)-4-[(4-fluorophenyl)methyl]-2,9,9-trimethyl-3,5- dioxa-4-boratricyclo[6.1.1.0A[2,6]]decane as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In diethyl ether at 20℃; for 24h; | |
91% | In diethyl ether at 20℃; | 2.2 Step 2:Synthesis of benzylboronic acid-(1S,2S,3R,5S)-(+)-2,3-decanol ester (B-3) Compound B-2 (1 g, 4.58 mmol) was dissolved in diethyl ether (20 mL).After adding (1S, 2S, 3R, 5S)-(+)-2,3-decanediol (859 mg, 5.04 mmol), it was allowed to react at room temperature overnight. The reaction solution was washed twice with water, and then washed twice with saturated brine.After drying with anhydrous sodium sulfate, concentration is reduced.Purified by silica gel column chromatography (eluent: PE/EtOAc = 50:1)The product was obtained as a colorless oil, 1.13 g, yield 91% |
91% | In diethyl ether at 20℃; Inert atmosphere; |
In tert-butyl methyl ether at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tert-butyl methyl ether at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.98% | In toluene at 55℃; for 3h; | 4.3 Step 3. 2, 3, 4, 5-tetrafluoro-6- ( (3aR, 4R, 6R) -3a, 5, 5-trimethylhexahydro-4, 6-methanobenzo [d] [1, 3, 2] dioxaborol-2-yl) aniline Into a 250-mL round-bottom flask was placed (2-amino-3, 4, 5, 6-tetrafluorophenyl) boronic acid (11.82 g, 56.58 mmol) , (1S, 3R, 4S, 5S) -4, 6, 6-trimethylbicyclo [3.1.1] heptane-3, 4-diol (9.56 g, 56.58 mmol) and toluene (120 mL) . The mixture was stirred for 3h at 55 . The residue was concentrated under vacuum and purified by a silica gel column eluted with Hex/EA (v/v =20/1) . This resulted 17.08 g (87.98%yield) of 2, 3, 4, 5-tetrafluoro-6- ( (3aR, 4R, 6R) -3a, 5, 5-trimethylhexahydro-4, 6-methanobenzo [d] [1, 3, 2] dioxaborol-2-yl) aniline as brown solid. LCMS: m/z= 344 [M+1] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.98% | In toluene at 55℃; for 3h; | 4.3 Step 3. 2, 3, 4, 5-tetrafluoro-6- ( (3aR, 4R, 6R) -3a, 5, 5-trimethylhexahydro-4, 6-methanobenzo [d] [1, 3, 2] dioxaborol-2-yl) aniline Into a 250-mL round-bottom flask was placed (2-amino-3, 4, 5, 6-tetrafluorophenyl) boronic acid (11.82 g, 56.58 mmol) , (1S, 3R, 4S, 5S) -4, 6, 6-trimethylbicyclo [3.1.1] heptane-3, 4-diol (9.56 g, 56.58 mmol) and toluene (120 mL) . The mixture was stirred for 3h at 55 . The residue was concentrated under vacuum and purified by a silica gel column eluted with Hex/EA (v/v =20/1) . This resulted 17.08 g (87.98%yield) of 2, 3, 4, 5-tetrafluoro-6- ( (3aR, 4R, 6R) -3a, 5, 5-trimethylhexahydro-4, 6-methanobenzo [d] [1, 3, 2] dioxaborol-2-yl) aniline as brown solid. LCMS: m/z= 344 [M+1] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In diethyl ether at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 20℃; for 16h; | 2-[(3R)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-4,7-dihydro-3H-oxaborepin-7-yl]acetic acid (15) General procedure: tert-Butyl (Z)-3-[tert-butyl(dimethyl)silyl]oxy-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hex-4-enoate (10). To a stirred solution of compound 2 (770mg, 4.58mmol) in THF (25mL) was added (+)-pinanediol (980mg, 4.58mmol) at room temperature. The reaction mixture was stirred for 16h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) on silica gel to give compound 10 (1g, 2.75mmol, 59.9% yield). | |
In tetrahydrofuran at 20℃; for 16h; | 2-[(3R)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-4,7-dihydro-3H-oxaborepin-7-yl]acetic acid (15) General procedure: tert-Butyl (Z)-3-[tert-butyl(dimethyl)silyl]oxy-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hex-4-enoate (10). To a stirred solution of compound 2 (770mg, 4.58mmol) in THF (25mL) was added (+)-pinanediol (980mg, 4.58mmol) at room temperature. The reaction mixture was stirred for 16h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) on silica gel to give compound 10 (1g, 2.75mmol, 59.9% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.2% | With anhydrous potassium acetate; palladium diacetate; dicyclohexyl(2’,4’,6’-triisopropyl-[ 1,1’-bi-phenyl]-2-yl)phosphane In tetrahydrofuran at 20 - 60℃; for 1.5h; | 78 A suspension of [3-(4-aminocinnolin-7-yl)-2-fluoro-4-methoxyphenyl]boronic acid (82.0 mg, 0.260 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (43.7 mg, 0.260 mmol) in THF (3.214 mL) was stirred at room temperature for 1h, then at 60°C for 30 min and then it was evaporated in vacuo. The residue was triturated with Et2O, filtered and washed with Et2O. The resulting yellow powder was purified by coulmn chromatography (KP-sil silica gel, 2 x SNAP10 in series) eluting with a gradient of EtOH in EtOAc from 0% to 20%. The appropriate fractions were concentrated and the residue was suspended in water and evaporated using a V10 evaporator to give 7-{2-fluoro-6-methoxy-3- [(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0,]decan-4- yl]phenyl}cinnolin-4-amine (49.6 mg, 0.111 mmol, 43.2% yield) as a yellowish solid. 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3 H), 1.10 (d, J = 10.78 Hz, 1H), 1.29 (s, 3 H), 1.44 (s, 3 H), 1.78 - 1.95 (m, 2 H), 2.07 - 2.12 (m, 1 H), 2.21 - 2.28 (m, 1 H), 2.35 - 2.45 (m, 1H), 3.82 (s, 3 H), 4.53 (d, J = 6.82 Hz, 1H), 7.08 (d, J = 8.58 Hz, 1H), 7.21 (s, 2 H), 7.53 (d, J = 8.58 Hz, 1H), 7.73 (dd, J = 8.25, 7.15 Hz, 1H), 7.97 (s, 1 H), 8.22 (d, J = 8.80 Hz, 1H), 8.64 (s, 1 H). LC-MS (Method A): r.t.0.89 min, MS (ESI) m/z = 448.24 [M+H] +. |
43.2% | With anhydrous potassium acetate; palladium diacetate; dicyclohexyl(2’,4’,6’-triisopropyl-[ 1,1’-bi-phenyl]-2-yl)phosphane In tetrahydrofuran at 20 - 60℃; for 1.5h; | 78 A suspension of [3-(4-aminocinnolin-7-yl)-2-fluoro-4-methoxyphenyl]boronic acid (82.0 mg, 0.260 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (43.7 mg, 0.260 mmol) in THF (3.214 mL) was stirred at room temperature for 1h, then at 60°C for 30 min and then it was evaporated in vacuo. The residue was triturated with Et2O, filtered and washed with Et2O. The resulting yellow powder was purified by coulmn chromatography (KP-sil silica gel, 2 x SNAP10 in series) eluting with a gradient of EtOH in EtOAc from 0% to 20%. The appropriate fractions were concentrated and the residue was suspended in water and evaporated using a V10 evaporator to give 7-{2-fluoro-6-methoxy-3- [(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0,]decan-4- yl]phenyl}cinnolin-4-amine (49.6 mg, 0.111 mmol, 43.2% yield) as a yellowish solid. 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3 H), 1.10 (d, J = 10.78 Hz, 1H), 1.29 (s, 3 H), 1.44 (s, 3 H), 1.78 - 1.95 (m, 2 H), 2.07 - 2.12 (m, 1 H), 2.21 - 2.28 (m, 1 H), 2.35 - 2.45 (m, 1H), 3.82 (s, 3 H), 4.53 (d, J = 6.82 Hz, 1H), 7.08 (d, J = 8.58 Hz, 1H), 7.21 (s, 2 H), 7.53 (d, J = 8.58 Hz, 1H), 7.73 (dd, J = 8.25, 7.15 Hz, 1H), 7.97 (s, 1 H), 8.22 (d, J = 8.80 Hz, 1H), 8.64 (s, 1 H). LC-MS (Method A): r.t.0.89 min, MS (ESI) m/z = 448.24 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.67% | In tetrahydrofuran at 20℃; for 3h; | 54 A suspension of [3-(4-aminocinnolin-7-yl)-4-methoxyphenyl]boronic acid (100.0 mg, 0.340 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (57.69 mg, 0.340 mmol) in THF (4 mL) was stirred at room temperature for three hours (after 1 hour the suspension became a clear solution) then the mixture was concentrated in vacuo. The residue was triturated with diethyl ether, the solvent was decanted and the solid residue was collected and dried to give 7-{2-methoxy-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0,]decan-4-yl]phenyl}cinnolin-4-amine (97 mg, 0.226 mmol, 66.67% yield) as an off white solid. 1H NMR (400 MHz, Methanol-d4) δ 0.94 (s, 3H), 1.24 (d, J = 10.88 Hz, 1H), 1.35 (s, 3H), 1.51 (s, 3H), 1.93 - 2.02 (m, 2H), 2.15 (t, J = 5.43 Hz, 1H), 2.26 - 2.34 (m, 1H), 2.48 (dd, J = 13.17, 9.68 Hz, 1H), 3.91 (s, 3H), 4.52 (dd, J = 8.79, 1.79 Hz, 1H), 7.19 (d, J = 8.20 Hz, 1H), 7.80 (dd, J = 8.79, 1.71 Hz, 1H), 7.82 - 7.88 (m, 2H), 8.14 (d, J = 8.76 Hz, 1H), 8.18 (d, J = 1.68 Hz, 1H), 8.60 (s, 1H). LC-MS (Method A): r.t.0.90 min, MS (ESI) m/z = 430.18 [M+H]+. |
66.67% | In tetrahydrofuran at 20℃; for 3h; | 54 A suspension of [3-(4-aminocinnolin-7-yl)-4-methoxyphenyl]boronic acid (100.0 mg, 0.340 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (57.69 mg, 0.340 mmol) in THF (4 mL) was stirred at room temperature for three hours (after 1 hour the suspension became a clear solution) then the mixture was concentrated in vacuo. The residue was triturated with diethyl ether, the solvent was decanted and the solid residue was collected and dried to give 7-{2-methoxy-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0,]decan-4-yl]phenyl}cinnolin-4-amine (97 mg, 0.226 mmol, 66.67% yield) as an off white solid. 1H NMR (400 MHz, Methanol-d4) δ 0.94 (s, 3H), 1.24 (d, J = 10.88 Hz, 1H), 1.35 (s, 3H), 1.51 (s, 3H), 1.93 - 2.02 (m, 2H), 2.15 (t, J = 5.43 Hz, 1H), 2.26 - 2.34 (m, 1H), 2.48 (dd, J = 13.17, 9.68 Hz, 1H), 3.91 (s, 3H), 4.52 (dd, J = 8.79, 1.79 Hz, 1H), 7.19 (d, J = 8.20 Hz, 1H), 7.80 (dd, J = 8.79, 1.71 Hz, 1H), 7.82 - 7.88 (m, 2H), 8.14 (d, J = 8.76 Hz, 1H), 8.18 (d, J = 1.68 Hz, 1H), 8.60 (s, 1H). LC-MS (Method A): r.t.0.90 min, MS (ESI) m/z = 430.18 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.88% | In tetrahydrofuran at 45℃; for 48h; | 101 A suspension of [3-(4-aminocinnolin-7-yl)-4-(difluoromethoxy)phenyl]boronic acid (700.0 mg, 2.11 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (359.96 mg, 2.11 mmol) in THF (28 mL) was stirred at 45°C overnight, then the mixture was concentrated in vacuo. The residue was triturated with diethyl ether. The solid was collected by filtration and dried in an oven at 45°C for 48h to give 7-{2-difluoromethoxy-5- [(1S,2S,6R,8S)-2,9,9-trimethyl-3,5- dioxa-4-boratricyclo[6.1.1.02,6]decan-4- yl]phenyl}cinnolin-4-amine (658 mg, 1.414 mmol, 66.88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3H), 1.07 - 1.13 (m, 1 H), 1.29 (3 H, s), 1.46 (3 H, s), 1.87 (d, J = 14.75 Hz, 1H) 1.92 (br. s, 1 H), 2.11 (t, J = 5.50 Hz, 1H), 2.20 - 2.28 (m, 1 H), 2.41 (dd, J = 14.31, 8.80 Hz, 1H), 4.57 (dd, J = 8.69, 1.65 Hz, 1H), 7.25 (s, 2 H), 7.31 (t, J = 72.8 Hz 1 H) 7.41 (d, J = 8.58 Hz, 1H), 7.69 (dd, J = 8.80, 1.76 Hz, 1H), 7.81 - 7.86 (m, 2 H), 8.10 (d, J = 1.54 Hz, 1H), 8.26 (d, J = 8.80 Hz, 1H), 8.65 (s, 1 H). LC-MS (Method A): r.t.0.92 min, MS (ESI) m/z= 466.25 [M+H]+. |
66.88% | In tetrahydrofuran at 45℃; for 48h; | 101 A suspension of [3-(4-aminocinnolin-7-yl)-4-(difluoromethoxy)phenyl]boronic acid (700.0 mg, 2.11 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (359.96 mg, 2.11 mmol) in THF (28 mL) was stirred at 45°C overnight, then the mixture was concentrated in vacuo. The residue was triturated with diethyl ether. The solid was collected by filtration and dried in an oven at 45°C for 48h to give 7-{2-difluoromethoxy-5- [(1S,2S,6R,8S)-2,9,9-trimethyl-3,5- dioxa-4-boratricyclo[6.1.1.02,6]decan-4- yl]phenyl}cinnolin-4-amine (658 mg, 1.414 mmol, 66.88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3H), 1.07 - 1.13 (m, 1 H), 1.29 (3 H, s), 1.46 (3 H, s), 1.87 (d, J = 14.75 Hz, 1H) 1.92 (br. s, 1 H), 2.11 (t, J = 5.50 Hz, 1H), 2.20 - 2.28 (m, 1 H), 2.41 (dd, J = 14.31, 8.80 Hz, 1H), 4.57 (dd, J = 8.69, 1.65 Hz, 1H), 7.25 (s, 2 H), 7.31 (t, J = 72.8 Hz 1 H) 7.41 (d, J = 8.58 Hz, 1H), 7.69 (dd, J = 8.80, 1.76 Hz, 1H), 7.81 - 7.86 (m, 2 H), 8.10 (d, J = 1.54 Hz, 1H), 8.26 (d, J = 8.80 Hz, 1H), 8.65 (s, 1 H). LC-MS (Method A): r.t.0.92 min, MS (ESI) m/z= 466.25 [M+H]+. |
Tags: 18680-27-8 synthesis path| 18680-27-8 SDS| 18680-27-8 COA| 18680-27-8 purity| 18680-27-8 application| 18680-27-8 NMR| 18680-27-8 COA| 18680-27-8 structure
[ 22422-34-0 ]
(1R,2R,3S,5R)-2,6,6-Trimethylbicyclo[3.1.1]heptane-2,3-diol
Similarity: 1.00
[ 106615-13-8 ]
1-Methyl-2-(tert-pentyl)cyclohexanol
Similarity: 0.89
[ 473-61-0 ]
2,6,6-Trimethylbicyclo[3.1.1]heptan-3-ol
Similarity: 0.89
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :