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. : | 1263166-90-0 | MDL No. : | MFCD26142970 |
Formula : | C10H14O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NSVXZMGWYBICRW-ULKQDVFKSA-N |
M.W : | 150.22 | Pubchem ID : | 53380994 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
94% | With pyridine In dichloromethane | |
93% | With pyridine In dichloromethane at 23℃; for 0.333333h; | 1.1.1.4 Synthesis of BCN-0(CO)0(4-N02-Ph) (28) - ((1 R,8S,9s)-bicyclo[6.1 .0]non-4-yn-9- yl)methyl (4-nitrophenyl) carbonate [00175] To a solution of 100 mg (0.666 mmol, 1 .0 eq) ((1 R,8S,9S)- bicyclo[6.1 .0]non-4-yn-9-yl)methanol in 16.6 mL dry CH2CI2 was added 134 μ (1 .664 mmol, 2.5 eq) pyridine and 168 mg (0.831 mmol, 1 .25 eq) 4-nitrophenyl chloroformate and the mixture was stirred for 20 min at 23°C, before it was quenched by addition of 20 mL saturated ammonium chloride solution. The mixture was extracted with CH2CI2 (3x 20 mL), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography through silicagel (PE:EtO Ac/95 :5 - 9:1 ) yielding 196 mg (0.6215 mmol, 93%) of 28 as a highly viscous liquid, slowly solidifying giving an amorphous white solid. (0289) [00176] BCN-0(CO)0(4-N02-Ph) (28): TCL (PE:EtOAc/9:1 ) Rf: 0.50 [UV254, CAM], IR (ATR) [cm"1]: 2918, 2852, 1760, 1616, 1595, 1523, 1492, 1470, 1440, 1354, 1340, 1323, 1247, 1203, 1 164, 1 139, 1 108, 1056, 1027, 1013, 989, 944, 921 , 859, 817, 776, 733, 703, 670, 628. 1H-NMR (700 MHz, CDCI3) δ [ppm]: 8.29 - 8.24 (m, 2H), 7.44 - 7.35 (m, 2H), 4.38 (d, J = 8.3 Hz, 2H), 2.36 - 2.26 (m, 4H), 2.25 - 2.19 (m, 2H), 1 .64 - 1 .54 (m, 2H), 1 .49 (p, J = 8.6 Hz, 1 H), 1 .09 - 0.99 (m, 2H). 13C-NMR (176 MHz, CDCI3) δ [ppm]: 155.73, 152.70, 145.49, 125.45, 121 .91 , 98.85, 68.16, 29.18, 21 .50, 20.65, 17.38. |
89% | With pyridine In N,N-dimethyl-formamide Inert atmosphere; |
87% | With pyridine In dichloromethane at 20℃; for 0.5h; | 4 Example 4: (1 fl,8S,9S)-Bicyclo[6.1.0]non-4-yn-9-ylmethyl (4-nitrophenyl) carbonate (endo- 13) Example 4: (1 fl,8S,9S)-Bicyclo[6.1.0]non-4-yn-9-ylmethyl (4-nitrophenyl) carbonate (endo- 13) To a solution of endo-12 (170 mg, 1 .13 mmol) in CH2CI2 (10 mL) was added pyridine (228 μ, 2.83 mmol) and 4-nitrophenyl chloroformate (251 mg, 1.24 mmol). After stirring at rt for 30 min the reaction mixture was quenched with saturated NH4CI solution and extracted with CH2CI2 (3 x 20 mL). The combined organic layers were dried with MgS04 and concentrated in vacuo. The crude product was purified by column chromatography (hexanes: EtOAC, 4: 1 ) to afford endo-13 as a colourless oil, that solidified overnight (310 mg, 0.98 mmol, 87%). Rf O.75 (hexanes: EtOAC, 2: 1 ); 1H NMR (500 MHz; CDCI3) δ 8.28 (2 H, d, J 9.2), 7.41 (2 H, d, J 9.2), 4.41 (2 H, d, J 8.3), 2.34-2.23 (6 H, m), 1.65-1.57 (2 H, m), 1 .55-1.49 (2 H, m), 1 .09-1 .04 (2 H, m). |
85% | With pyridine In dichloromethane at 20℃; for 0.25h; | |
84% | With pyridine In dichloromethane at 20℃; for 4h; Inert atmosphere; | 33 Example 33: Preparation of Compound BCN-PNP (1R,8S,9s)-Bicyclo[6.1.0]non-4-yn-9-ylmethanol (800 mg, 5.3 mmol) was dissolved in DCM (125 mL) at room temperature under N2 atmosphere. Pyridine (1.22 mL, 15.9 mmol, 3.0 eq.) and 4-nitrophenyl chloroformate (1.75 g, 8.74 mmol, 1.6 eq.) were added thereto. After the mixture was stirred for 4 hours at the same temperature, the reaction was quenched by the addition of saturated NH4Cl solution (100 mL) and extracted with EA (100 mL×4). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (Hex:EA=10:1) to obtain compound BCN-PNP (1.34 g, 84%) as white solid. |
84% | With pyridine In dichloromethane at 20℃; for 4h; Inert atmosphere; | 47 Example 47; Preparation of Compound BCN-PNP (lR,8S,9s)-Bicyclo[6. l .0]non-4-yn-9-yl methanol (800 mg, 5.3 mmol) was dissolved in DCM (125 mL) at room temperature under N2 atmosphere. Pyridine (1.22 mL, 15.9 mmol) and 4-nitrophenyl chloroformate (1.75 g, 8.74 mmol) were added thereto. After the mixture was stirred for 4 hours at the same temperature, the reaction was quenched by the addition of saturated NH4Cl solution (100 mL) and extracted with EA (100 mL x 4). The organic layer was dried over Na^SO-i, filtered and concentrated in vacuo. The residue was purified by column chromatography (Hex: EA = 10: 1) to obtain compound BCN-PNP (1.34 g, 84 %) as white solid. NMR (600 MHz, CDCb) d 8.29 (d, J= 9 Hz, 2H), 7.39 (d, J= 9 Hz, 2H), 4.41 (d, J = 8.4 Hz, 2H), 2.36 - 2.24 (m, 6H), 1.62 - 1.55 (m, 2H), 1.53 - 1.49 (m, 1H), 1.07 (t, = 10.2 Hz, 2H). |
77% | With pyridine In dichloromethane at 20℃; for 0.25h; Inert atmosphere; | |
74% | With pyridine In dichloromethane at 20℃; for 0.5h; | 1.1; 2.1; 3.1 1) Activation of BCN: Dissolve 5 mmol of BCN in 100 mL of anhydrous dichloromethane. And adding 15mmol of pyridine, After stirring for a few minutes, add 6 mmol of p-nitrophenyl chloroformate (pNC). Reaction at room temperature for 30 min;After the end, add saturated ammonium chloride solution, extraction, The organic phase is dried over anhydrous sodium sulfate. Steamed, Separated and purified by silica gel column chromatography The white solid BCN-pNC was obtained in a yield of 74%. |
62% | With pyridine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; | |
60% | With pyridine In dichloromethane at 0℃; for 3h; | |
59% | With pyridine In dichloromethane at 20℃; for 1h; | |
39% | With pyridine In dichloromethane at 0℃; | 1 To a cooled (0 °C) solution of 4-nitrophenyl chloroformate (30.5 g, 151 mmol) in DCM (500 mL) was added pyridine (24.2 mL, 23.7 g, 299 mmol). A solution of BCN-OH (101 , 18.0 g, 120 mmol) in DCM (200 mL) was added dropwise to the reaction mixture. After the addition was completed, a saturated aqueous solution of NH4CI (500 mL) and water (200 mL) were added. After separation, the aqueous phase was extracted with DCM (2 c 500 mL). The combined organic phases were dried (Na2SC>4) and concentrated. The crude material was purified by silica gel chromatography and the desired product 102 was obtained as an off-white solid (18.7 g, 59 mmol, 39%). 1H NMR (400 MHz, CDCI3) d (ppm) 8.32-8.23 (m, 2H), 7.45-7.34 (m, 2H), 4.40 (d, J = 8.3 Hz, 2H), 2.40-2.18 (m, 6H), 1.69- 1.54 (m, 2H), 1.51 (quintet, J = 9.0 Hz, 1 H), 1.12-1.00 (m, 2H) |
39% | With pyridine In dichloromethane at 0℃; | 1 Example 1. Synthesis of compound 102 To a cooled (0 °C) solution of 4-nitrophenyl chloroformate (30.5 g, 151 mmol) in DCM (500 mL) was added pyridine (24.2 mL, 23.7 g, 299 mmol). A solution of BCN-OH (101 , 18.0 g, 120 mmol) in DCM (200 mL) was added dropwise to the reaction mixture. After the addition was completed, a saturated aqueous solution of NFUCI (500 mL) and water (200 mL) were added. After separation, the aqueous phase was extracted with DCM (2 c 500 mL). The combined organic phases were dried (Na2S04) and concentrated. The crude material was purified by silica gel chromatography and the desired product 102 was obtained as an off-white solid (18.7 g, 59 mmol, 39%). 1H NMR (400 MHz, CDCI3) d (ppm) 8.32-8.23 (m, 2H), 7.45-7.34 (m, 2H), 4.40 (d, J = 8.3 Hz, 2H), 2.40-2.18 (m, 6H), 1.69- 1.54 (m, 2H), 1.51 (quintet, J = 9.0 Hz, 1 H), 1.12-1.00 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 3h; Reflux; Inert atmosphere; | |
54% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 85℃; for 2h; Inert atmosphere; | |
205 mg | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; Inert atmosphere; Reflux; |
With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 2h; Reflux; | 1 After straightforward separation by silica gel, first the endo-isomer of Ila.l was converted into alcohol IIa.2 following a straightforward three-step procedure of reduction, bromination and elimination. Thus, ester reduction of endo-lla.1 with L1AIH4 (30 min) gave a crude intermediate alcohol (30 min) that was pure enough for bromination without intermediate purification (30 min). It must be noted that temporary protection of the alcohol, as in the synthesis of DIBO, is not required. Finally, the resulting dibromide was subjected to excess KOiBu in THF (0 °C · reflux, 2 h), affording the desired 9-(hydroxymethyl)- bicyclo[6.1.0]non-4-yne endo-lla.2 in 61% isolated yield for the three steps from endo- Ila.l. A similar sequence of events, that can be executed in a single day with only one chromatographic purification, afforded the diastereomeric exoisomer of IIa.2 in 53%. | |
With potassium <i>tert</i>-butylate In tetrahydrofuran for 2h; Reflux; | ||
With potassium <i>tert</i>-butylate In tetrahydrofuran at 70℃; for 2h; Inert atmosphere; | ||
With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 70℃; for 2h; | ||
1.48 g | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 75℃; for 2.5h; Inert atmosphere; | 1.S22 Synthesis of (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol: The endo intermediate, (lR,8S,9s,Z)-ethyl bicyclo[6.1.0]non-4-ene-9-carboxylate (3.70 g, 19.0 mmol), was dissolved in 0°C anhydrous ether (65 mL). Lithium aluminum hydride (750 mg, 19.8 mmol, 1.04x) in 0°C anhydrous ether (130 mL) was added dropwise to the ester over 15 minutes and the reaction was stirred at room temperature for 20 minutes. Minimal water was added to quench the solution and induced the formation of a grey precipitate. The solution was dried over MgS04, filtered, and concentrated in vacuo to yield the crude alcohol intermediate (lR,8,S',,Z)-bicyclo[6.1.0]non-4-en-9- ylmethanol (2.91 g, 19.1 mmol, quantitative yield). A solution of bromine (3.1 g, 1.0 mL, 19 mmol) in DCM (13 mL) and added dropwise to a 0°C solution of the crude hydroxyl intermediate dissolved in anhydrous DCM (140 mL) until a yellow color persisted. The reaction was quenched with aqueous sodium thiosulfate (10 wt %, 50 mL). The product was extracted into DCM (2 x 70 mL), dried over MgS04, filtered, and concentrated in vacuo to yield the crude dibromide intermediate ((lR,8,S',95)-4,5-dibromobicyclo[6.1.0]nonan-9-yl)methanol (5.8 g, 19 mmol, quantitative yield). The dibromide intermediate was dissolved in 0°C anhydrous THF (120 mL) to which a solution of potassium tert-butoxide (1 M in THF, 50 mL) was added dropwise. The reaction mixture was stirred while refluxing at 75°C for 2.5 hours. The solution was cooled to room temperature and quenched with saturated aqueous ammonium chloride (150 mL). THF was removed in vacuo and the product was extracted into DCM (3 x 70 mL), dried over MgS04, filtered, and concentrated. The product was purified on a silica column (0-20% ethyl acetate in hexanes) and concentrated to yield pure (R,8S,9s)- bicyclo[6.1.0]non-4-yn-9-ylmethanol as a yellow oil (1.48 g, 9.85 mmol, 52% yield over 3 steps). 1H MR (500 MHz, CDC13) δ 3.62 (d, J=7.7 Hz, 2H), 2.59 (br s, 1H), 2.16 (m, 6H), 1.50 (m, 2H), 1.22 (m, 1H), 0.84 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bis-[(trifluoroacetoxy)iodo]benzene In methanol; water at 20℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: dirhodium tetraacetate / dichloromethane / 0 °C 2: lithium aluminium tetrahydride / diethyl ether / 0.5 h / 0 °C 3: bromine / dichloromethane 4: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / 0 °C / Reflux | ||
Multi-step reaction with 4 steps 1: dirhodium tetraacetate / dichloromethane / 40 h / 20 °C 2: lithium aluminium tetrahydride / diethyl ether 3: bromine / dichloromethane / 0 °C 4: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / Reflux | ||
Multi-step reaction with 4 steps 1: dirhodium tetraacetate / dichloromethane / 48 h / 0 - 20 °C / Inert atmosphere 2: lithium aluminium tetrahydride / diethyl ether / 0.25 h / 0 - 20 °C / Inert atmosphere 3: bromine / dichloromethane / 0 °C 4: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / 70 °C / Inert atmosphere |
Multi-step reaction with 4 steps 1: dirhodium tetraacetate / dichloromethane / 3 h / 20 °C / Reflux 2: lithium aluminium tetrahydride / tetrahydrofuran / 1.17 h / 0 - 20 °C 3: bromine / dichloromethane / 20 °C 4: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 0 °C / Reflux; Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: rhodium(II) acetate / dichloromethane / 0 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / diethyl ether / 0 - 20 °C 2.2: 0.08 h / 20 °C 2.3: 1.5 h / 0 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: C12H18O2 With diisobutylaluminium hydride In diethyl ether at 0 - 20℃; Stage #2: With bromine In dichloromethane at 20℃; for 0.0833333h; Stage #3: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1.5h; Reflux; | |
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / diethyl ether / 0.5 h / 0 °C 2: bromine / dichloromethane 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / 0 °C / Reflux | ||
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / diethyl ether / 0.25 h / 0 - 20 °C / Inert atmosphere 2: bromine / dichloromethane / 0 °C 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / 70 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / diethyl ether / 0 - 45 °C 1.2: 0 °C 2.1: potassium <i>tert</i>-butylate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: bromine / dichloromethane 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / 0 °C / Reflux | ||
Multi-step reaction with 2 steps 1: bromine / dichloromethane / 0 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 4h; | 16 endo-Bicyclo[6.1.0]non-4-yn-9-yl-formaldehyde (17) To a cooled (0 °C) suspension of BCN-methanol (180 mg, 1.20 mmol) in CH2Cl2 (10 mL) is added Dess-Martin periodinane (0.68 g, 1.6 mmol) and the suspension is stirred for 4 h at rt. After this time, water (10 mL) is added, the solvent layers are separated and the CH2Cl2 layer is dried on MgS04 and filtered. The filtrate is concentrated in vacuo at 0 °C and the residue is purified by column chromatography on silica gel (CH2Cl2) to afford 17 as a white solid (53 mg, 30%). 1H NMR (CDCl3, 300 MHz): 59.6 (d, 1 H), 2.33-2.22 (m, 9H), 1.57-1.54 (m, 3H). |
With Dess-Martin periodane In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: biotin With benzotriazol-1-ol In N,N-dimethyl-formamide at 60℃; for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide for 3h; Inert atmosphere; Molecular sieve; Stage #3: (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol With dmap In dichloromethane; N,N-dimethyl-formamide at 20 - 60℃; for 28h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol; C72H92CoN16O13P In water; N,N-dimethyl-formamide at 20℃; for 16h; Stage #2: benzyl azide With copper(l) iodide; tris[(1-benzyl-1H-1,2,3-triazol-4yl)methyl]amine In water; N,N-dimethyl-formamide for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83% 2: 6% 3: 5% | In tetrahydrofuran at 20℃; for 3h; | 14 Example 14. Reaction of bisazide 25 with 6b and 26b To a solution of BCN alcohol 6b (28 mg, 0.188 mmol) and DIB AC derivative 26b (60 mg, 0.188 mmol) in THF (2 mL) was added a solution of bisazide 25 (34 mg, 0.094 mmol) in THF (1 mL). The mixture was stirred at rt for 3 h, when TLC analysis indicated complete conversion. LCQ analysis of the crude reaction mixture indicated the formation of three new products, with the major peak corresponding to that of compound 26 (M+H+ = 833) and minor peaks indicative of double SPAAC of 25 with 6b (M+H+ = 665) and double SPAAC of 25 with 26b (M+H+ = 1001). The reaction mixture was concentrated and purified by two consecutive silica gel column chromatography purifications (column 1 : MeOH/DCM/PhCH3 1 : 10:4, column 2: MeOH/DCM/PhCH3 1 :8: 1), leading to the isolation of 26 as a pure compound (65 mg, 83%). RF 0.26 (MeOH/DCM/PhCH3 1 :8: 1). 1H NMR (CDC13, 400 MHz): δ 8.79, 8.77, 8.72 (3 d, J = 1.9 Hz, 1H), 8.37-8.33 (m, 1H), 8.19-8.15 (m, 1H), 7.65-7.23 (m, 8H), 7.16-7.10 (m, 1H), 6.36-6.27 (m, 1H), 6.1 1-5.97 (m, 1H), 4.74-3.95 (m, 4H), 3.83-3.47 (m, 10H), 3.29-3.13 (m, 2H), 3.01-2.89 (m, 1H), 2.78-2.48 (m, 2H), 2.36-2.26 (m, 1H), 2.19-1.73 (m, 8H), 1.65-1.52 (m, 2H), 1.26-0.98 (m, 3H) ppm. 13C NMR (CDC13, 125 MHz): δ 171.7, 171.3, 170.5, 170.4, 164.4, 164.1, 145.7, 145.6, 145.3, 145.2, 144.9, 144.8, 143.3, 141.2, 139.8, 138.0, 137.7, 136.3, 136.2, 136.1, 135.5, 135.2, 133.4, 133.3, 133.2, 133.1, 132.8, 132.1, 131.9, 131.8, 131.7, 131.5, 131.3, 131.0, 130.5, 130.4, 130.3, 130.1, 129.9, 129.8, 129.7, 129.5, 128.9, 128.7, 128.6, 128.4, 127.9, 127.7, 127.3, 124.8, 124.7, 124.6, 70.6, 70.4, 70.3, 70.1, 69.8, 69.5, 69.3, 68.4, 68.3, 59.7, 52.8, 51.6, 49.1, 48.5, 40.7, 40.5, 35.0, 34.9, 34.2, 34.0, 26.2, 26.1, 23.6, 23.5, 23.4, 23.3, 23.0, 22.8, 22.7, 22.3, 22.2, 21.6, 21.5, 20.1, 20.0, 19.9. HRMS (ESI+) m/z calcd for C43H49Nio08 (M + H)+: 833.3735, found: 833.3739. Besides 26 also bis-BCN (6b) and bis-DIBAC (26b) adducts were isolated. Bis-BCN adduct (26 + 2x6b, 4.0 mg, 6%): R/0.19 (MeOH/DCM/PhCH3 1 :8: 1). 1H NMR (CDC13, 400 MHz): δ 8.72 (dd, J = 1.8, 1.1 Hz, 1H), 8.41 (dd, J = 8.2, 2.0 Hz, 1H), 8.05-8.01 (m, 1H), 7.52 (d, J = 8.2 Hz, 1H), 4.47-4.39 (m, 2H), 3.94 (t, J = 5.4 Hz, 2H), 3.81-3.53 (m, 12H), 3.26 (ddd, J = 15.8, 7.6, 3.2 Hz, 1H), 3.07 (ddd, J = 15.7, 7.9, 3.3 Hz, 1H), 3.00-2.93 (m, 2H), 2.85- 2.66 (m, 3H), 2.60 (ddd, J = 16.1, 10.3, 3.2 Hz), 2.36-2.12 (m, 4H), 1.58-1.47 (m, 3H), 1.25-0.98 (m, 7H) ppm. HRMS (ESI+) m/z calcd for C33H45N807 (M + H)+: 665.3411, found: 665.3439. Bis-DIBAC adduct (26 + 2x26b, 5 mg, 5%): Rf 0.31 (MeOH/DCM/PhCH3 1 :8: 1). 1H NMR (CDC13, 400 MHz): δ 8.77-8.64 (m, 1H), 8.34- 8.11 (m, 1H), 8.09 (d, J = 1.4 Hz, 1H), 7.92-7.83 (m, 1H), 7.67-6.92 (m, 16H), 6.45- 5.89 (m, 2H), 5.56-5.51, 5.03-4.90 (2 x m, 1H), 4.76-4.65 (m, 2H), 4.58-4.26 (m, 3H), 4.18-3.92 (m, 1H), 3.82-3.08 (m, 12H), 2.82-2.36 (m, 1H), 2.12-1.73 (m, 8H), 1.33- 1.25 (m, 2H) ppm. HRMS (ESI+) m/z calcd for C53H52Ni2Na09 (M + Na)+: 1023.3878, found: 1023.3856. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In [D3]acetonitrile; water-d2 at 20℃; | 15-1 Example 15-1. Competition experiment between 3-azido-N-benzyl-3,3- difluoropropanamide (19c) and 2-azido-N-benzylacetamide (19b) with BCN-OH (35) Example 15-1. Competition experiment between 3-azido-N-benzyl-3,3- difluoropropanamide (19c) and 2-azido-N-benzylacetamide (19b) with BCN-OH (35) 2-Azido-N-benzylacetamide 19b (1.85 mg, 9.70 μηιο) and 3-azido-N-benzyl-3,3- difluoropropanamide 19c (2.33 mg, 9.70 μιηο) were dissolved in CD3CN:D20 2: 1 (400 iV). Next, BCN-OH 35 (0.292 mg, 1.95 μιηο) was dissolved in 200 μL· CD3CN:D20 2: 1 and added to the reaction. The resulting solution was allowed to stir o.n. at r. , and concentrated in vacuo. The residue was taken up in CDC13 (700 μ.) and an 1H-NMR experiment was performed to check the ratio of the two formed triazole products, which indicated an approx. 2: 1 ratio of the triazole product resulting from 19c with 35 versus 36 (the triazole product resulting from 19b with 35). 1H-NMR (400 MHz, CDC13): δ 7.38-7.27 (m, 11H), 4.97 (d, J= 2 Hz, 0.15 H), 4.48 (d, J = 3.6 Hz, 3.69 H), 4.43 (d, J = 2.4 Hz, 0.38 H), 4.40 (d, J = 5.2 Hz, 0.20 H), 4.05 (s, 1.82 H), 3.79 (t, J = 13.2 Hz, 0.28 H), 3.74-3.65 (m, 0.51 H). The region of the spectrum at higher field remains undefined due to overlapping peaks. MS showed the presence of the two clicked products: LRMS (ESI+) calcd for C2oH24F2N402 ( +H+) 391.19, found 391.12 (triazole product resulting from 19c with 35), and calcd for Ci9H24N402 ( +H+) 341.20, found 341.19 (36). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With trimethylamine-N-oxide In dichloromethane for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In toluene at 20℃; for 0.0833333h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C10H16O With bromine In dichloromethane at 20℃; for 0.5h; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 21h; Reflux; Overall yield = 1.11 g; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In methanol; water at 20℃; for 0.5h; | Synthesis of compound 3: To a solution of 4-tert-butyl-1,2-benzoquinone (51 mg, 0.31 mmol) in MeOH/H2O (1:1) was added endo-bicyclo[6.1.0]non-4-yn-9-ylmethanol (endo-BCN, 2) (70 mg, 0.46 mmol, 1.5 eq.). The reaction mixture was stirred at rt for30 min. During the reaction the color changed from dark red to yellow. The reaction mixture was concentrated in vacuo.The residue was dry-loaded with silica and purified by column chromatography (1% triethylamine in EtOAc/pentane (1:2→ 1:1) to afford 3 as a yellow, glassy solid (77 mg, 0.24 mmol, 79% yield) as a mixture of exo,endo and endo,endodiastereoisomers (3a + 3b). RF 0.10 (heptane/EtOAc, 2:1). 1H NMR (CDCl3, 400 MHz): δ = 6.08-6.05 (m, 2H, diastereoisomera+b), 3.89-3.88 (m, 2H, diastereoisomer a + b), 3.73 (d, J = 6.4 Hz, 1H, diastereoisomer a), 3.73 (d, J= 6.4Hz, 1H, diastereoisomer b), 3.69-3.67 (m, 4H, diastereoisomer a + b), 2.87-2.72 (m, 4H, diastereoisomer a + b), 2.30-2.21(m, 4H, diastereoisomer a + b), 2.13-2.01 (m, 4H, diastereoisomer a + b), 1.80-1.68 (m, 4H, diastereoisomer a + b),1.13 (s, 9H, diasteroisomer a), 1.12 (s, 9H, diasteroisomer b), 1.14-1.04 (m, 2H, diastereoisomer a + b), 0.89-0.68 (m,4H). 13C NMR (CDCl3, 125 MHz): δ = 182.6, 182.5, 181.5, 181.3, 154.1, 153.8, 136.6, 136.4, 136.2, 135.7, 118.5, 118.4,60.8, 60.4, 59.9, 59.9, 58.1, 58.0, 34.9, 34.9, 32.3, 32.2, 32.1, 31.64, 31.5, 28.3, 28.2, 22.7, 22.4, 22.3, 22.3, 20.2, 20.1,17.9, 17.6, 17.3, 16.7. HRMS (CI) for C20H26O3: (M + H+-CO), calcd: 287.2006, found: 287.1996; (M+CH2CH3+), calcd:343.2273, found: 343.2290; (M + CH2CH3+-CO) calcd: 315.2319, found: 315.2297. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine In dichloromethane for 2.5h; | 36 Example 36. Synthesis of(61) To a solution of 57 (0.15 g, 1.0 mmol) in DCM (15 mL) was added CSI (87 1iL, 0.14 g,1.0 mmol), Et3N (279 jL, 202 mg, 2.0 mmol) and a solution of H2N-PEG3-OH (251 mg,1.3 mmol) in DCM (1 mL). After stirring for 2.5 h, the reaction mixture was quenched through addition of a solution ofNH4C1 (sat., 20 mL). After separation, the aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried (Na2504) and concentrated. The residue was purified by gradient column chromatography (0 -10% MeOH in DCM). Product 61 was obtained as colorless thick oil (254 mg, 0.57 mmol, 57%). ‘H NMR (400 IVIFIz, CDC13) (ppm) 6.81 (br. s, 1H), 4.26 (d, J= 8.2 Hz, 2H), 3.80-3.70 (m, 4H), 3.70-3.58 (m, 1OH), 3.36 (t, J = 4.7 Hz, 2H), 2.36-2.16 (m, 6H),1.64-1.49 (m, 2H), 1.40 (quintet, J= 8.7 Hz, 1H), 1.04-0.92 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | To a stirring solution of 57 (500 mg, 3.33 mmol) in DCM (100 mL) was added CSI (290 tL, 471 mg, 3.33 mmol). After 20 mi Et3N (1.4 mL, 1.0 g, 10 mmol) and a solution of diethanolamine.HC1 (571 mg, 4.0 mmol) in DMF (5 mL) were added subsequently. After an additional 45 mm., the reaction mixture was concentrated under reduced pressure and the residue was purified by gradient column chromatography (0 -* 15% MeOH in DCM).Product 66 was obtained as colorless thick oil (767 mg, 2.13 mmol, 64%). ?H NIVIR (400IVIFIz, CDC13) (ppm) 4.26 (d, J= 8.2 Hz, 2H), 3.87 (t, J= 4.9 Hz, 4H), 3.55 (t, J = 4.9Hz, 4H), 2.37-2.16 (m, 6H), 1.65-1.45 (m, 2H), 1.39 (quintet, J = 8.6 Hz, 1H), 1.05-0.92 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol In dichloromethane for 0.25h; Stage #2: With triethylamine In dichloromethane for 0.0833333h; Stage #3: 2-(2-Aminoethoxy)ethanol In dichloromethane for 0.25h; | 23 Example 23. Synthesis of compound 148 To a solution of BCN-OH (101) (3.0 g, 20 mmol) in DCM (300 mL) was added CSI (146) (1 .74 ml_, 2.83 g, 20 mmol). Afterthe mixture was stirred for 15 min, Et3N (5.6 mL, 4.0 g, 40 mmol) was added. The mixture was stirred for 5 min and 2-(2-aminoethoxy)ethanol (147) (2.2 mL, 2.3 g, 22 mmol) was added. The resulting mixture was stirred for 15 min and saturated aqueous NH4CI (300 mL) was added. The layers were separated, and the aqueous phase was extracted with DCM (200 mL). The combined organic layers were dried (Na2S04) and concentrated. The residue was purified by silica gel chromatography (0% to 10% MeOH in DCM). The fractions, containing the desired product, were concentrated. The residue was taken up in EtOAc (100 mL) and concentrated. The desired product 148 was obtained as a slightly yellow oil (4.24 g, 11.8 mmol, 59%). 1H NMR (400 MHz, CDCI3) d (ppm) 5.99-5.79 (bs, 1 H), 4.29 (d, J = 8.3 Hz, 2H), 3.78-3.74 (m, 2H), 3.66-3.56 (m, 4H), 3.37-3.30 (m, 2H), 2.36-2.16 (m, 6H), 1 .63-1 .49 (m, 2H), 1 .40 (quintet, J = 8.7 Hz, 1 H), 1 .05-0.94 (m, 2H). |
59% | Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol In dichloromethane for 0.25h; Stage #2: With triethylamine In dichloromethane for 0.0833333h; Stage #3: 2-(2-Aminoethoxy)ethanol In dichloromethane for 0.25h; | 26 Example 26. Synthesis of compound 148 To a solution of BCN-OH (101) (3.0 g, 20 mmol) in DCM (300 mL) was added CSI (146) (1 .74 ml_, 2.83 g, 20 mmol). Afterthe mixture was stirred for 15 min, Et3N (5.6 mL, 4.0 g, 40 mmol) was added. The mixture was stirred for 5 min and 2-(2-aminoethoxy)ethanol (147) (2.2 mL, 2.3 g, 22 mmol) was added. The resulting mixture was stirred for 15 min and saturated aqueous NH4CI (300 mL) was added. The layers were separated, and the aqueous phase was extracted with DCM (200 mL). The combined organic layers were dried (Na2S04) and concentrated. The residue was purified by silica gel chromatography (0% to 10% MeOH in DCM). The fractions, containing the desired product, were concentrated. The residue was taken up in EtOAc (100 mL) and concentrated. The desired product 148 was obtained as a slightly yellow oil (4.24 g, 11.8 mmol, 59%). 1H NMR (400 MHz, CDCI3) d (ppm) 5.99-5.79 (bs, 1 H), 4.29 (d, J = 8.3 Hz, 2H), 3.78-3.74 (m, 2H), 3.66-3.56 (m, 4H), 3.37-3.30 (m, 2H), 2.36-2.16 (m, 6H), 1 .63-1 .49 (m, 2H), 1.40 (quintet, J = 8.7 Hz, 1 H), 1.05-0.94 (m, 2H). |
57% | With triethylamine In dichloromethane for 0.166667h; Inert atmosphere; | 29 Example 29. Synthesis of(58) To a solution of 57 (1.5 g, 10 mmol) in DCM (150 mL), under a N2 atmosphere, was added CSI (0.87 mL, 1.4 g, 10 mmol), Et3N (2.8 mL, 2.0 g, 20 mmol) and 2-(2- aminoethoxy)ethanol (1.2 mL, 1.26 g, 12 mmol). The mixture was stirred for 10 mm and quenched through addition of aqueous NH4C1 (sat., 150 mL). After separation, the aqueous layers was extracted with DCM (150 mL). The combined organic layers weredried (Na2SO4) and concentrated. The residue was purified with column chromatography. Product 58 was obtained as slightly yellow thick oil (2.06 g, 5.72 mmol, 57%). ‘HNMR (400 IVIHz, CDC13) E(ppm)6.0(bs, 1H), 4.28 (d,J= 8.2 Hz, 2H), 3.78-3.73 (m, 2H), 3.66-3.61 (m, 2H), 3.61-3.55 (m, 2H), 3.34 (t, J = 4.9 Hz, 2H), 2.37-2.15 (m, 6H), 1.64-1.48 (m, 2H), 1.40 (quintet, J= 8.7 Hz, 1H), 1.05-0.92 (m, 2H). |
57% | With triethylamine In dichloromethane for 0.166667h; Inert atmosphere; | 1 Example 1. Preparation of compound 6 To a solution of BCN-OH (5, 1.5 g, 10 mmol) in DCM (150 mL), under a N2 atmosphere, was added CSI (0.87 mL, 1.4 g, 10 mmol), EtsN (2.8 mL, 2.0 g, 20 mmol) and 2-(2-aminoethoxy)ethanol (1.2 mL, 1.26 g, 12 mmol). The mixture was stirred for 10 min and quenched through addition of aqueous NH4CI (sat., 150 mL). After separation, the aqueous layer was extracted with DCM (150 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified with column chromatography. Product 6 was obtained as slightly yellow thick oil (2.06 g, 5.72 mmol, 57%). 1 H NMR (400 MHz, CDCh) 6 (ppm) 6.0 (bs, 1 H), 4.28 (d, J = 8.2 Hz, 2H), 3.78-3.73 (m, 2H), 3.66-3.61 (m, 2H), 3.61-3.55 (m, 2H), 3.34 (t, J = 4.9 Hz, 2H), 2.37-2.15 (m, 6H), 1.64-1.48 (m, 2H), 1 .40 (quintet, J = 8.7 Hz, 1 H), 1.05-0.92 (m, 2H). |
57% | With triethylamine In dichloromethane for 0.166667h; Inert atmosphere; | 1 Example 1. Preparation of compound 6 To a solution of BCN-OH (5, 1.5 g, 10 mmol) in DCM (150 mL), under a N2 atmosphere, was added CSI (0.87 mL, 1.4 g, 10 mmol), EtsN (2.8 mL, 2.0 g, 20 mmol) and 2-(2-aminoethoxy)ethanol (1.2 mL, 1.26 g, 12 mmol). The mixture was stirred for 10 min and quenched through addition of aqueous NH4CI (sat., 150 mL). After separation, the aqueous layer was extracted with DCM (150 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified with column chromatography. Product 6 was obtained as slightly yellow thick oil (2.06 g, 5.72 mmol, 57%). 1 H NMR (400 MHz, CDCh) 6 (ppm) 6.0 (bs, 1 H), 4.28 (d, J = 8.2 Hz, 2H), 3.78-3.73 (m, 2H), 3.66-3.61 (m, 2H), 3.61-3.55 (m, 2H), 3.34 (t, J = 4.9 Hz, 2H), 2.37-2.15 (m, 6H), 1.64-1.48 (m, 2H), 1 .40 (quintet, J = 8.7 Hz, 1 H), 1.05-0.92 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83% 2: 6% 3: 5% | In tetrahydrofuran at 20℃; for 3h; | 14 Reaction of Bisazide 25 with 6b and 26b To a solution of BCN alcohol 6b (28 mg, 0.188 mmol) and DIBAC derivative 26b (60 mg, 0.188 mmol) in THF (2 mL) was added a solution of bisazide 25 (34 mg, 0.094 mmol) in THF (1 mL). The mixture was stirred at rt for 3 h, when TLC analysis indicated complete conversion. LCQ analysis of the crude reaction mixture indicated the formation of three new products, with the major peak corresponding to that of compound 26 (M+H+=833) and minor peaks indicative of double SPAAC of 25 with 6b (M+H+=665) and double SPAAC of 25 with 26b (M+H+=1001). The reaction mixture was concentrated and purified by two consecutive silica gel column chromatography purifications (column 1: MeOH/DCM/PhCH3 1:10:4, column 2: MeOH/DCM/PhCH3 1:8:1), leading to the isolation of 26 as a pure compound (65 mg, 83%). RF 0.26 (MeOH/DCM/PhCH3 1:8:1). 1H NMR (CDCl3, 400 MHz): δ 8.79, 8.77, 8.72 (3×d, J=1.9 Hz, 1H), 8.37-8.33 (m, 1H), 8.19-8.15 (m, 1H), 7.65-7.23 (m, 8H), 7.16-7.10 (m, 1H), 6.36-6.27 (m, 1H), 6.11-5.97 (m, 1H), 4.74-3.95 (m, 4H), 3.83-3.47 (m, 10H), 3.29-3.13 (m, 2H), 3.01-2.89 (m, 1H), 2.78-2.48 (m, 2H), 2.36-2.26 (m, 1H), 2.19-1.73 (m, 8H), 1.65-1.52 (m, 2H), 1.26-0.98 (m, 3H) ppm. 13C NMR (CDCl3, 125 MHz): δ 171.7, 171.3, 170.5, 170.4, 164.4, 164.1, 145.7, 145.6, 145.3, 145.2, 144.9, 144.8, 143.3, 141.2, 139.8, 138.0, 137.7, 136.3, 136.2, 136.1, 135.5, 135.2, 133.4, 133.3, 133.2, 133.1, 132.8, 132.1, 131.9, 131.8, 131.7, 131.5, 131.3, 131.0, 130.5, 130.4, 130.3, 130.1, 129.9, 129.8, 129.7, 129.5, 128.9, 128.7, 128.6, 128.4, 127.9, 127.7, 127.3, 124.8, 124.7, 124.6, 70.6, 70.4, 70.3, 70.1, 69.8, 69.5, 69.3, 68.4, 68.3, 59.7, 52.8, 51.6, 49.1, 48.5, 40.7, 40.5, 35.0, 34.9, 34.2, 34.0, 26.2, 26.1, 23.6, 23.5, 23.4, 23.3, 23.0, 22.8, 22.7, 22.3, 22.2, 21.6, 21.5, 20.1, 20.0, 19.9. HRMS (ESI+) m/z calcd for C43H49N10O8(M+H)+: 833.3735. found: 833.3739. Besides 26 also bis-BCN (6b) and bis-DIBAC (26b) adducts were isolated. Bis-BCN adduct (26+2×6b, 4.0 mg, 6%): Rf0.19 (MeOH/DCM/PhCH3 1:8:1). 1H NMR (CDCl3, 400 MHz): δ 8.72 (dd, J=1.8, 1.1 Hz, 1H), 8.41 (dd, J=8.2, 2.0 Hz, 1H), 8.05-8.01 (m, 1H), 7.52 (d, J=8.2 Hz, 1H), 4.47-4.39 (m, 2H), 3.94 (t, J=5.4 Hz, 2H), 3.81-3.53 (m, 12H), 3.26 (ddd, J=15.8, 7.6, 3.2 Hz, 1H), 3.07 (ddd, J=15.7, 7.9, 3.3 Hz, 1H), 3.00-2.93 (m, 2H), 2.85-2.66 (m, 3H), 2.60 (ddd, J=16.1, 10.3, 3.2 Hz), 2.36-2.12 (m, 4H), 1.58-1.47 (m, 3H), 1.25-0.98 (m, 7H) ppm. HRMS (ESI+) m/z calcd for C33H45N5O7 (M+H)+: 665.3411. found: 665.3439. Bis-DIBAC adduct (26+2×26b, 5 mg, 5%): Rf 0.31 (MeOH/DCM/PhCH3 1:8:1). 1H NMR (CDCl3, 400 MHz): δ 8.77-8.64 (m, 1H), 8.34-8.11 (m, 1H), 8.09 (d, J=1.4 Hz, 1H), 7.92-7.83 (m, 1H), 7.67-6.92 (m, 16H), 6.45-5.89 (m, 2H), 5.56-5.51, 5.03-4.90 (2×m, 1H), 4.76-4.65 (m, 2H), 4.58-4.26 (m, 3H), 4.18-3.92 (m, 1H), 3.82-3.08 (m, 12H), 2.82-2.36 (m, 1H), 2.12-1.73 (m, 8H), 1.33-1.25 (m, 2H) ppm. HRMS (ESI+) m/z calcd for C53H52N12NaO9 (M+Na)+: 1023.3878. found: 1023.3856. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In [D3]acetonitrile; water-d2 at 20℃; | 15.1 Example 15-1 Competition experiment between 3-azido-N-benzyl-3, 3-difluoropropanamide (19c) and 2-azido-N-benzylacetamide (19b) with BCN-OH (35) (0345) 2-Azido-N-benzylacetamide 19b (1.85 mg, 9.70 μmol) and 3-azido-N-benzyl-3,3-difluoropropanamide 19c (2.33 mg, 9.70 μmol) were dissolved in CD3CN:D2O 2:1 (400 μL). Next, BCN-OH 35 (0.292 mg, 1.95 μmol) was dissolved in 200 μL CD3CN:D2O 2:1 and added to the reaction. The resulting solution was allowed to stir o.n. at r.t., and concentrated in vacuo. The residue was taken up in CDCl3 (700 μL) and an 1H-NMR experiment was performed to check the ratio of the two formed triazole products, which indicated an approx. 2:1 ratio of the triazole product resulting from 19c with 35 versus 36 (the triazole product resulting from 19b with 35). (0346) 1H-NMR (400 MHz, CDCl3): δ 7.38-7.27 (m, 11H), 4.97 (d, J=2 Hz, 0.15H), 4.48 (d, J=3.6 Hz, 3.69H), 4.43 (d, J=2.4 Hz, 0.38H), 4.40 (d, J=5.2 Hz, 0.20H), 4.05 (s, 1.82H), 3.79 (t, J=13.2 Hz, 0.28H), 3.74-3.65 (m, 0.51H). The region of the spectrum at higher field remains undefined due to overlapping peaks. MS showed the presence of the two clicked products: LRMS (ESI+) calcd for C20H24F2N4O2 (M+H+) 391.19. found 391.12 (triazole product resulting from 19c with 35), and calcd for C19H24N4O2 (M+H+) 341.20. found 341.19 (36). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 1h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 1h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | A solution of BCN alcohol (0.384 g, 2.55 mmole) in MeCN (25 mL) under a N2 atmosphere was cooled to 0 C, and chlorosulfonyl isocyanate was added (CSI) was added dropwise (0.255 mL, 415 mg, 2.93 mmole, 1.15 equiv.). After stirring for 15 minutes, Et3N was added dropwise (1.42 mL, 1.03 g, 10.2 mmole, 4 equiv.) and stirring was continued for another 10 minutes. Next, a solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (1.0 g, 6.1 mmole, 2.4 equiv.) in H2O (5 mL) was added and the reaction mixture was stirred to room temperature for 2 h. After this time, CHCI3 (50 mL) and H2O (100 mL) were added, and the layers were separated. To the aqueous layer in a separatory funnel was added CH2CI2 (100 mL) and the pH was adjusted to 4 with 1 N HCI, before separation of layers. The water layer was extracted twice with CH2CI2 (2chi100 mL), the organic layers were combined and dried (Na2S04), filtered and concentrated. The residue was purified by flask column chromatography on silica, elution with CH2Cl2 to 20% MeOH in CH2CI2. Yield 0.42 g (1.0 mmole, 39%) of 126 as a colourless sticky wax. | |
39% | A solution of BCN alcohol (0.384 g, 2.55 mmole) in MeCN (25 mL) under a N2atmosphere was cooled to 0 C, and chlorosulfonyl isocyanate was added (CSI) was added dropwise (0.255 mL, 415 mg, 2.93 mmole, 1 .15 equiv.). After stirring for 15 minutes, Et3N was added dropwise (1.42 mL, 1.03 g, 10.2 mmole, 4 equiv.) and stirring was continued for another 10 minutes. Next, a solution of 2-(2-(2- aminoethoxy)ethoxy)acetic acid (1.0 g, 6.1 mmole, 2.4 equiv.) in H2O (5 mL) was added and the reaction mixture was stirred to room temperature for 2 h. After this time, CHCI3 (50 mL) and H2O (100 mL) were added, and the layers were separated. To the aqueous layer in a separatory funnel was added CH2CI2 (100 mL) and the pH was adjusted to 4 with 1 N HCI, before separation of layers. The water layer was extracted twice with CH2CI2 (2 100 mL), the organic layers were combined and dried (Na2S04), filtered and concentrated. The residue was purified by flask column chromatography on silica, elution with CH2CI2to 20% MeOH in CH2CI2Yield 0.42 g (1.0 mmole, 39%) of 3 as a colorless sticky wax. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In chloroform at 25℃; for 10h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water at 23℃; | 2 Example 2: Rapid strain induced sydnone-alkyne cycloaddition reactions forbioorthogonal PET imaging Diverse variety of arylsydnones were synthesized and their reactionkinetics were studied with BCN. The cycloaddition reactions were conducted inmethanol: water (55:45) at room temperature (23 °C). Table 1 lists the calculatedsecond order rate kinetics associated with the cycloaddition reaction between BCNand various sydnone derivatives |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In acetonitrile; at 20℃;Inert atmosphere; | (lR,8^,95)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (1.48 g, 9.9 mmol) and Ν,Ν'- Disuccinimidyl carbonate (5.1 g, 19.9 mmol, 2x) were dissolved in acetonitrile (75 mL) under a nitrogen atmosphere. Triethylamine (3.3g, 4.5 mL, 32 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with 1 : 1 ethyl acetate: ether (200 mL) and washed with water (6 x 100 mL) and brine (2 x 50 mL). The organic layer was dried over MgS04, filtered, and concentrated in vacuo. The product was purified on a silica flash column (3 : 1 hexanes:ethyl acetate) to yield the product [(lR,8S,9S)-bicyclo[6.1.0]non-4-yn-9-yl]methyl 2,5-dioxopyrrolidin-l-yl carbonate (denoted BCN-OSu) as a white solid (1.72 g, 5.9 mmol, 60% yield). 1H NMR (500 MHz, CDC13): δ 4.48 (d, J=8.4 Hz, 2H), 2.87 (s, 4H), 2.30 (m, 6H), 1.57 (m, 3H), 1.09 (m, 2H). These spectral data matched those previously reported. |
27% | With triethylamine; In acetonitrile; for 2.33333h; | To a solution of BCN-OH (101 , 21.0 g, 0.14 mol) in MeCN (450 mL) were added disuccinimidyl carbonate (53.8 g, 0.21 mol) and triethylamine (58.5 mL, 0.42 mol). After the mixture was stirred for 140 minutes, it was concentrated in vacuo and the residue was co-evaporated once with MeCN (400 mL). The residue was dissolved in EtOAc (600 mL) and washed with H20 (3 x 200 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 4% EtOAc in DCM) and gave 108 (11 .2 g, 38.4 mmol, 27% yield) as a white solid. NMR (400 MHz, CDCI3): d (ppm) 4.45 (d, 2H, J = 8.4 Hz), 2.85 (s, 4H), 2.38- 2.18 (m, 6H), 1.65- 1.44 (m, 3H), 1.12-1.00 (m, 2H). |
27% | With triethylamine; In acetonitrile; for 2.33333h; | To a solution of BCN-OH (101 , 21.0 g, 0.14 mol) in MeCN (450 ml_) were added disuccinimidyl carbonate (53.8 g, 0.21 mol) and triethylamine (58.5 ml_, 0.42 mol). After the mixture was stirred for 140 minutes, it was concentrated in vacuo and the residue was co-evaporated once with MeCN (400 ml_). The residue was dissolved in EtOAc (600 ml_) and washed with H20 (3 c 200 ml_). The organic layer was dried over Na2SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 4% EtOAc in DCM) and gave 108 (11.2 g, 38.4 mmol, 27% yield) as a white solid. NMR (400 MHz, CDCI3): d (ppm) 4.45 (d, 2H, J = 8.4 Hz), 2.85 (s, 4H), 2.38- 2.18 (m, 6H), 1.65- 1.44 (m, 3H), 1.12-1.00 (m, 2H). |
With triethylamine; In acetonitrile; at 20℃;Inert atmosphere; | The procedure was done according to published procedure molecules 2013,18, 7346-7363 with several changes. To 400 mg of BCN-OH (2.66 mmol) 10 ml ofacetonitrile were added followed by addition of 1 .5m1 triethylamine. To reaction solution 1.70 gr of DSC (6.64 mmol) were added and reaction was stirred under inert conditions. Reaction solution was stirred at ambient temperature for overnight before completion as was observed by TLC (TLC mobile phase: 50% Ethyl Acetate, 50%hexane; Staining PMA). Reaction solution was evaporated to dryness by rotovapor. Then reaction residue was dissolved in 5 ml of chloroform and added with 50 ml of diethyl ether. The reaction mixture was stirred for 15 minutes and residue stayed in the flask while reaction solution was evaporated to dryness by rotovapor. The obtained solid - 950 mg (yield about 95%) According to TLC the purity was morethan 90-95% therefore the product was used as is the next step/steps. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In aq. phosphate buffer; dimethyl sulfoxide at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol; 5'-O-(triisopropylsilyl)-3'-O-azidomethyl-5-(perylen-3-ylethynyl)-2'-deoxyuridine In dimethyl sulfoxide for 0.0833333h; Stage #2: With tetrabutyl ammonium fluoride; water In dimethyl sulfoxide at 20℃; Overall yield = 73 %; Overall yield = 52 mg; | 4.2.7 General procedure for the copper-free cycloaddition reaction of 5 with the corresponding bicyclononyne derivative. General procedure: To a solution of 5 (70mg, 0.10mmol) in DMSO (2mL) bicyclononyne derivative (16mg, 0.11mmol) was added and the resulting mixture was stirred for 5min. The solution was poured in the mixture of EtOAc (50mL) and water (20mL), the organic layer was washed with water (2×20mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (0→30% EtOAc in CH2Cl2). The intermediate product obtained was dissolved in DMSO (2mL) and TBAF·3H2O was added (34mg, 0.11mmol). After stirring overnight the mixture was diluted with H2O (10mL) and placed into the refrigerator (+4°C) for several hours. The solid precipitated was filtered, washed with water (2×5mL), diethyl ether (2×5mL) and hexane (2×5mL), and then dried in vacuum affording the corresponding product 8 as a mixture of inseparable diastereomers |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | A solution of BCN alcohol (0.384 g, 2.55 mmole) in MeCN (25 mL) under a N2 atmosphere was cooled to 0 C, and chlorosulfonyl isocyanate was added (CSI) was added dropwise (0.255 mL, 415 mg, 2.93 mmole, 1.15 equiv.). After stirring for 15 minutes, EtsN was added dropwise (1 .42 mL, 1.03 g, 10.2 mmole, 4 equiv.) and stirring was continued for another 10 minutes. Next, a solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (1 .0 g, 6.1 mmole, 2.4 equiv.) in H2O (5 mL) was added and the reaction mixture was stirred to room temperature for 2 h. After this time, CHCI3 (50 mL) and H2O (100 mL) were added, and the layers were separated. To the aqueous layer in a separatory funnel was added CH2CI2 (100 mL) and the pH was adjusted to 4 with 1 N HCI, before separation of layers. The water layer was extracted twice with CH2CI2 (2 chi 100 mL), the organic layers were combined and dried (Na2SC>4), filtered and concentrated. The residue was purified by flask column chromatography on silica, elution with CH2CI2 to 20% MeOH in CH2CI2. Yield 0.42 g (1 .0 mmole, 39%) of 3 as a colorless sticky wax. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In methanol at 20℃; for 12h; | A mixture of Naph-Syd 1b (44 mg, 0.13 mmol) and endo-BCN 7 (15 mg, 0.10 mmol) in methanol (10 mL), was stirred for 12 h. After reaction, evaporated the methanol, and the residue was purified by semi-preparative RP-HPLC (5.0 mL min-1 and 80%CH3CN/H2O as eluents) to afford yellow solid in 81% yield (2c, 36 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | In ethyl acetate at 25℃; for 360h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.1% | In ethyl acetate at 25℃; for 2h; UV-irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.3% | In ethyl acetate at 25℃; for 2h; UV-irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.2% | In ethyl acetate at 25℃; for 360h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | In ethyl acetate at 25℃; for 360h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.9% | In ethyl acetate at 25℃; for 360h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | In ethyl acetate at 25℃; for 360h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In ethyl acetate at 25℃; for 360h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | In ethyl acetate at 25℃; for 360h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol; 4-Carboxybenzaldehyde With diisopropyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With dmap In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In chloroform at 25℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With pyridine In dichloromethane at -20 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In chloroform at 20℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. 4.1.1. (10,10a,11,11a,12,13-hexahydro-9H-cyclopropa[5',6']cycloocta[1',2':3,4]pyrazolo[5,1-a]isoquinolin-11-yl)methanol (Pyr1) The title compound Pyr1 was obtained in 88% yield (64.1 mg,0.22 mmol) from compound Syd1 (46.5 mg, 0.25 mmol) according to the general procedure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc 7/3). 1H NMR (400 MHz, CDCl3, δ ppm): 8.28 (d, J = 8.0 Hz, 1H), 8.09 (4, J = 7.4 Hz, 1H), 7.67 (dd, J = 7.3 Hz, J = 1.0 Hz, 1H), 7.51 (m, 2H), 6.83 (d, J = 7.4 Hz, 1H), 3.78 (m, 2H), 3.35 (m, 1H), 3.19 (m, 2H), 3.04 (m, 1H), 2.44 (m, 1H), 2.33 (m, 1H), 1.79 (m, 2H), 1.15 (quint., J = 8.2 Hz, 1H), 1.02-0.92 (m, 2H). 13C NMR (100 MHz, CDCl3, δ ppm): 154.4, 134.5, 129.6, 127.4, 127.3,127.1,126.4, 125.8, 123.1,112.7,110.7, 60.1, 27.2, 23.8, 23.4, 23.1, 21.2, 19.0, 18.9. IR (cm-1): 3343, 1224, 1489, 1476, 1366, 1021, 186, 772, 729. LCMS (ESI): m/z: 293 [M+H]+. Mp.: 131-133 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In chloroform at 20℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In chloroform at 20℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In chloroform at 50℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In chloroform at 20℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In chloroform at 20℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In chloroform at 20℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In chloroform at 20℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In chloroform at 50℃; for 48h; Inert atmosphere; | 4.1. General procedure for the preparation of pyrazoles adducts with BCN General procedure: To a solution of the sydnone (1.0 equiv.) in CHCl3 (0.1 M) was added (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) (1.05 equiv.). The mixture was stirred at room temperature during 48 h and evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In dimethyl sulfoxide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In dimethyl sulfoxide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h / 0 °C | ||
Multi-step reaction with 3 steps 1: pyridine / N,N-dimethyl-formamide / Inert atmosphere 2: triethylamine / N,N-dimethyl-formamide / 1.5 h / 25 °C / Inert atmosphere 3: methanol; lithium hydroxide; water / 16 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 1.5h; | 1 l-Acetyl-5-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-yl]methoxy}-4,6-dibromo-1H- indole-3-yl 2,3,4,6-tetra-O-acetyl- b -D-glucopyranoside (29). Diisopropyl azodicarboxylate (39.4 pL, 0.20 mmol) was added to a solution of 18 (67.9 mg, 0.10 mmol), 28 (16.5 mg, 0.11 mmol), and PPI13 (52.5 mg, 0.20 mmol) in CH2CI2 (0.50 mL) at room temperature. After 1.5 h, the reaction mixture was passed through silica (ethyl acetate as an eluent). The eluent was concentrated and again chromatographed [silica, hexanes/acetone (2:1) followed by hexanes/ethyl acetate (1: 1)] to afford a white solid (51.1 mg, 63%): 1H NMR (400 MHz, CDCI3) d 1.09-1.1 (m, 2H), 1.60-1.82 (m, 3H), 2.05 (s, 3H), 2.07 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.18-2.40 (m, 6H), 2.60 (s, 3H), 3.89 (ddd, J = 2.3, 5.1, 9.7 Hz, 1H), 4.10 (d, J = 7.2 Hz, 2H), 4.20 (dd, J = 5.1, 12.5 Hz, 1H), 4.38 (dd, J = 2.3, 12.5 Hz, 1H), 5.06 (d, / = 7.6 Hz, 1H), 5.21 (dd, / = 9.2, 9.7 Hz, 1H), 5.31 (dd, / = 9.2, 9.2 Hz, 1H), 5.39 (dd, / = 7.6, 9.2 Hz, 1H), 7.25 (s, 1H), 8.70 (br s, 1H); 13C NMR (175 MHz, CDCI3) d 19.2, 20.7, 20.8, 20.9, 21.1, 21.7, 23.9, 29.5, 62.0, 68.3, 70.9, 72.0, 72.6, 72.7, 99.1, 100.3, 107.9, 112.0, 116.6, 120.4, 123.2, 131.0, 140.5, 150.1, 168.0, 169.4, 169.6, 170.4, 170.6; ESI-MS obsd 810.0761, calcd 810.0755 [(M + H)+, M = CgBNO]. |
63% | With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 1.5h; | 1 1-Acetyl-5-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-yl]methoxy}-4,6-dibromo-1H- indole-3-yl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (29). Diisopropyl azodicarboxylate (39.4 μL, 0.20 mmol) was added to a solution of 18 (67.9 mg, 0.10 mmol), 28 (16.5 mg, 0.11 mmol), and PPh3 (52.5 mg, 0.20 mmol) in CH2Cl2 (0.50 mL) at room temperature. After 1.5 h, the reaction mixture was passed through silica (ethyl acetate as an eluent). The eluent was concentrated and again chromatographed [silica, hexanes/acetone (2:1) followed by hexanes/ethyl acetate (1:1)] to afford a white solid (51.1 mg, 63%): 1H NMR (400 MHz, CDCl3) δ 109-11 (m 2H) 160-182 (m 3H) 205 (s 3H) 207 (s 3H) 209 (s 3H) 211 (s, 3H), 2.18-2.40 (m, 6H), 2.60 (s, 3H), 3.89 (ddd, J = 2.3, 5.1, 9.7 Hz, 1H), 4.10 (d, J = 7.2 Hz, 2H), 4.20 (dd, J = 5.1, 12.5 Hz, 1H), 4.38 (dd, J = 2.3, 12.5 Hz, 1H), 5.06 (d, J = 7.6 Hz, 1H), 5.21 (dd, J = 9.2, 9.7 Hz, 1H), 5.31 (dd, J = 9.2, 9.2 Hz, 1H), 5.39 (dd, J = 7.6, 9.2 Hz, 1H), 7.25 (s, 1H), 8.70 (br s, 1H); 13C NMR (175 MHz, CDCl3) δ 19.2, 20.7, 20.8, 20.9, 21.1, 21.7, 23.9, 29.5, 62.0, 68.3, 70.9, 72.0, 72.6, 72.7, 99.1, 100.3, 107.9, 112.0, 116.6, 120.4, 123.2, 131.0, 140.5, 150.1, 168.0, 169.4, 169.6, 170.4, 170.6; ESI-MS obsd 810.0761, calcd 810.0755 [(M + H)+, M = C34H37Br2NO12]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol; 1-acetyl-4,6-dibromo-5-hydroxy-1H-indol-3-yl 2,3,4-tri-O-acetyl-β-D-glucopyranosiduronic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 3h; Stage #2: With methanol; potassium carbonate In dichloromethane at 20℃; for 1.5h; | 2 5-[(1R,8S,9s)-Bicyclo[6.1.0]non-4-yn-9-yl]methoxy}-4,6-dibromo-1H-indole-3-yl β-D- glucopyranosiduronic acid methyl ester (5, route A) Diisopropyl azodicarboxylate (3.5 μL, 0.018 mmol) was added to a solution of 1- acetyl-4,6-dibromo-5-hydroxy-1H-indol-3-yl 2,3,4-tri-O-acetyl-β-D- glucopyranosiduronic acid methyl ester (7.0 mg, 0.11 mmol), (1R,8S,9s)- bicyclo[6.1.0]non-4-yn-9-ylmethanol (1.9 mg, 0.013 mmol), and PPh3 (4.7 mg, 0.018 mmol) in CH2Cl2 (105 μL) at room temperature. After 3 h, MeOH (420 μL) and K2CO3 (1.5 mg) were added. After 1.5 h, the reaction mixture was passed through silica gel [CH2Cl2/MeOH (2:1) as eluent]. The eluent was concentrated under reduced pressure. Preparative thin layer chromatography [silica gel, 0.25 mm, CHCl3/MeOH (10:1)] afforded a white solid (2.9 mg, 44%): 1H NMR (700 MHz, CD3OD) δ 0.98-1.09 (m, 2H), 1.64-1.80 (m, 3H), 2.13-2.23 (m, 2H), 2.23-2.38 (m, 4H), 3.49 (dd, J = 8.8, 9.4 Hz, 1H), 3.59 (dd, J = 8.0, 8.8 Hz, 1H), 3.66 (dd, J = 9.4, 9.6 Hz, 1H), 3.78 (s, 3H), 3.96 (d, J = 9.6 Hz, 1H), 4.09 (d, J = 7.8 Hz, 2H), 4.83 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.50 (s, 1H); 13C NMR (175 MHz, CD3OD) δ 20.2, 21.7, 22.0, 30.6, 52.9, 72.8, 73.0, 75.0, 76.8, 77.3, 99.6, 105.3, 107.9, 112.6, 115.4, 116.0, 120.1, 132.9, 138.5, 147.0, 171.1; ESI-MS obsd 650.0000, calcd 649.9996 [(M + Na)+, M = C25H27Br2NO8]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 1h; | 2 1-Acetyl-5-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-yl]methoxy}-4,6-dibromo-5-hydroxy- 1H-indol-3-yl 2,3,4-tri-O-acetyl-β-D- glucopyranosiduronic acid methyl ester (11). Diisopropyl azodicarboxylate (13 μL, 63 μmol) was added to a solution containing 4 (34 mg, 51 μmol), (1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethanol (9.3 mg, 62 μmol), and PPh3 (17 mg, 65 μmol) in CH2Cl2 (0.51 mL) at room temperature. The reaction mixture was stirred for 1 h and then quenched by the addition of H2O. The organic layer was washed with brine, dried (Na2SO4), and concentrated. Column chromatography (silica, hexanes with 0% to 4% acetone) afforded a white solid (28 mg, 69%): 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 7.35 (s, 1H), 5.47-5.31 (m, 3H), 5.14 (d, J = 7.0 Hz, 1H), 4.27 (d, J = 9.6 Hz, 1H), 4.10 (d, J = 7.8 Hz, 2H), 3.78 (s, 3H), 2.58 (s, 3H), 2.37-2.28 (m, 4H), 2.28-2.20 (m, 2H), 2.11 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 1.79-1.68 (m, 2H), 1.06 (dd, J = 11.4, 8.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol In dichloromethane for 0.25h; Stage #2: C29H61N3O14 With triethylamine In dichloromethane for 21.6h; | 49 Example 49. Synthesis of 190 To a solution of BCN-OH (164 mg, 1.10 mmol, 3 equiv.) in DCM (3 ml_) was added CSI (76 pl_, 0.88 mmol, 2.4 equiv.). After stirring for 15 minutes triethylamine (255 pl_, 5.50 mmol, 5 equiv.) was added. A solution of 189 was prepared by adding DCM (3 ml_) and triethylamine (508 pl_, 11.0 mmol, 10 equiv.). This stock solution was added to the original reaction mixture after 6 minutes. After stirring the mixture for 21 .5 hours, it was concentrated in vacuo. The residue was purified by silicagel column chromatography (0% 10% MeOH in DCM). Product 190 was obtained in 39% yield as pale yellow oil (165.0 mg, 139 pmol). LCMS (ESI+) calculated for C43H72NsOi8S2+ (M+H+) 1186.54, found 1186.65. 1H-NMR (400 MHz, CDCI3): d (ppm) 6.09 - 5.87 (m, 2H), 4.31 - 4.19 (m, 6H), 3.76 - 3.50 (m, 50H), 3.40 - 3.29 (m, 4H), 2.38 - 2.16 (m, 12H), 1.66 - 1.47 (m, 4H), 1 .40 (quintet, J 8.0 Hz, 2H), 1.04 - 0.94 (m, 4H). |
39% | Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol In dichloromethane for 0.25h; Stage #2: C29H61N3O14 With triethylamine In dichloromethane for 21.5h; | 51-2 Example 51-2. Synthesis of 190 To a solution of BCN-OH (164 mg, 1.10 mmol, 3 equiv.) in DCM (3 mL) was added CSI (76 pL, 0.88 mmol, 2.4 equiv.). After stirring for 15 minutes triethylamine (255 pL, 5.50 mmol, 5 equiv.) was added. A solution of 189 was prepared by adding DCM (3 mL) and triethylamine (508 pL, 11.0 mmol, 10 equiv.). This stock solution was added to the original reaction mixture after 6 minutes. After stirring the mixture for 21 .5 hours, it was concentrated in vacuo. The residue was purified by silicagel column chromatography (0% 10% MeOH in DCM). Product 190 was obtained in 39% yield as pale yellow oil (165.0 mg, 139 pmol). LCMS (ESI+) calculated for C43H72NsOi8S2+ (M+H+) 1186.54, found 1186.65. 1H-NMR (400 MHz, CDCI3): d (ppm) 6.09 - 5.87 (m, 2H), 4.31 - 4.19 (m, 6H), 3.76 - 3.50 (m, 50H), 3.40 - 3.29 (m, 4H), 2.38 - 2.16 (m, 12H), 1.66 - 1.47 (m, 4H), 1 .40 (quintet, J = 8.0 Hz, 2H), 1.04 - 0.94 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol In dichloromethane for 0.5h; Stage #2: C17H37N3O8 With triethylamine In dichloromethane for 0.75h; | 72 Example 72. Synthesis of 329 To a solution of 101 (18 mg, 0.12 mmol) in DCM (1 mL) was added chlorosulfonyl isocyanate (CSI). After 30 min, Et3N (37 mI_, 27 mg, 0.27 mmol) was added. To a solution of 195 (26 mg, 0.054 mmol) in DCM (1 mL) was added Et3N (37 pL, 27 mg, 0.27 mmol). This mixture was added to the reaction mixture. After 45 min, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (DCM to 7% MeOH in DCM). Product 329 was obtained as a colorless film (27 mg, 0.029 mmol, 54%). LCMS (ESI+) calculated for C39H64N5Oi6S2+ (M+H+) 922.38, found 922.50. |
41% | Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol With triethylamine In dichloromethane at 20℃; for 0.133333h; Stage #2: C17H37N3O8 In dichloromethane at 20℃; for 21h; | 18 Example 18. Synthesis of compound 17 by CSI reaction of diamine 1 A solution of BCN-OH (0.32 g, 2.1 mmol, 2.5 equiv.) in dry CH2CI2 (5 ml_) was treated with CSI (177 pL, 2.0 mmol, 2.4 equiv.) and stirred at room temperature for 10 minutes. Nect, Et3N (592 pl_, 4.25 mmol, 5 equiv.) was added and after stirring for 8 minutes a solution of diamine 10 (412 mg, 0.85 mmol) in 6 ml_ dry CH2CI2 (this solution was pre-treated with triethylamine (615 mI_, 4.43 mmol, 5 equiv.) was added. The resulting reaction mixture was stirred for 21 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silicagel chromatography (0% 6% MeOH in CH2CI2). The desired product was obtained as a pale yellow oil (321.7 mg, 0.35 mmol; 41%). NMR (400 MHz, CDCI3 +few drops CD3OD) d (ppm) 4.34-4.20 (m, 6H), 3.76-3.68 (m, 4H), 3.68-3.57 (m, 18H), 3.57-3.49 (m, 4H), 3.34-3.23 (m, 4H), 2.37-2.14 (m, 12H), 1.66-1.49 (m, 4H), 1.40 (quintet, J = 8.7 Hz, 2H), 1.04-0.92 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol In dichloromethane at 20℃; for 0.25h; Stage #2: C17H37N3O8 With triethylamine In dichloromethane at 20℃; for 1.5h; | 82 Example 82. Synthesis of 341 Compound 101 (16.3 mg, 0.10 mmol) was dissolved in DCM (0.8 mL) and chlorosulfonyl isocyanate (8.6 pL, 0.099 mmol) was added at room temperature. After stirring for 15 min at room temperature, Et3N (69.0 mI_, 0.49 mmol) was added, followed by the addition of a mixture of 335 (40 mg, 0.099 mmol) dissolved in DCM (1 .0 ml_) and Et3N (69.0 mI_, 0.49 mmol). This mixture was stirred at room temperature for 1.5 h (mixture 1) to give crude 339. In another vial, 340 (DBCO-C2-OH, Broadpharm) (34.0 mg, 0.099 mmol) was dissolved in DCM (0.8 ml_) at room temperature and chlorosulfonyl isocyanate (7.75 mI_, 0.089 mmol) was added. After stirring at room temperature for 15 min, Et3N (69.0 mI_, 0.49 mmol) was added followed by crude 339. After stirring at room temperature for another 2 h, the reaction mixture was concentrated in vacuo and purified by flash column chromatography over silicagel (0% 15% MeOH in DCM) after which it was co-evaporated with EtOAC (2x) to completely remove the MeOH. Product 341 was obtained as a clear yellow oil (20.0 mg, 0.017 mmol, 17%). LCMS (ESI+) calculated for C5OH7ON70I8S2+ (M+H+) 1121.26 found (0485) 1121.59. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: isocyanate de chlorosulfonyle; (1R,8S,9S)‐bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol In dichloromethane for 0.25h; Stage #2: C21H45N3O10 With triethylamine In dichloromethane for 23h; | 70 Example 70. Synthesis of 325 To a solution of 101 (81 mg, 0.54 mmol, 2.3 equiv.) in DCM (2 ml_) was added CSI (43 mI_, 0.49 mmol, 2.1 equiv.). After stirring for 15 minutes triethylamine (164 mI_, 1.17 mmol, 5 equiv.) was added. A solution of 324 was prepared by adding DCM (2 ml_) and triethylamine (164 pl_, 1.17 mmol, 5 equiv.). This stock solution was added to the original reaction mixture after 6 minutes. After stirring the mixture for 23 hours, it was concentrated in vacuo. The residue was purified by silica gel column chromatography (0% --> 12% MeOH in DCM). Product 325 was obtained in 31% yield as pale yellow oil (73.0 mg, 72.2 pmol). LCMS (ESI+) calculated for C43H72N5Oi8S2+ (M+H+) 1010.43, found 1010.50. 1H-NMR (400 MHz, CDCI3): d (ppm) 6.21 - 5.85 (m, 2H), 4.38 - 4.17 (m, 6H), 3.80 - 3.57 (m, 30H), 3.57 - 3.44 (m, 4H), 3.44 - 3.30 (m, 4H), 2.38 - 2.16 (m, 12H), 1 .64 - 1 .48 (m, 4H), 1 .40 (quintet, J = 8.0 Hz, 2H), 1 .05 - 0.91 (m, 4H). |
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 :