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CAS No. : | 14970-87-7 | MDL No. : | MFCD00015873 |
Formula : | C6H14O2S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HCZMHWVFVZAHCR-UHFFFAOYSA-N |
M.W : | 182.30 | Pubchem ID : | 84733 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.98 |
TPSA : | 96.06 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.05 cm/s |
Log Po/w (iLOGP) : | 2.43 |
Log Po/w (XLOGP3) : | 0.51 |
Log Po/w (WLOGP) : | 0.88 |
Log Po/w (MLOGP) : | 0.61 |
Log Po/w (SILICOS-IT) : | 1.59 |
Consensus Log Po/w : | 1.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.83 |
Solubility : | 27.0 mg/ml ; 0.148 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.1 |
Solubility : | 1.46 mg/ml ; 0.00799 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.01 |
Solubility : | 1.78 mg/ml ; 0.00975 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.44 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P273-P301+P310+P330-P302+P352-P305+P351+P338 | UN#: | 3082 |
Hazard Statements: | H301-H315-H319-H411 | Packing Group: | Ⅲ |
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 |
---|---|---|
30% | With caesium carbonate In N,N-dimethyl-formamide at 45 - 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate In N,N-dimethyl-formamide at 55 - 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate; thiourea; In water; toluene; | EXAMPLE 21 1,8-dimercapto-3,6-dioxa octane 187 g (1 mol) of ethylene glycol-bis(2-chloroethyl)-ether and 182 g (2.4 mols) of thiourea in 1000 ml of water are maintained for 4 hours under reflux. The clear solution is cooled to 20 C. and 120 g of hydrazine hydrate are added. After adding 400 ml of toluene, the mixture is heated for 1 hour in the steam bath. The toluene phase is separated off, concentrated under reduced pressure and distilled under vacuum. Bp2: 105-115 C. Yield: 153 g (84%). According to the process described in Org. Syntheses 30, 35 (1950), in the form described by Dann and Chiesa, J. Org. Chem. 26, 1994 (1961), the yield amounts to from only 50 to 60% of the theoretical. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tripropylborane In methanol; hexane; benzene at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tripropylborane In methanol; hexane; benzene at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With hydrogenchloride; thiourea | |
Multi-step reaction with 2 steps 1.1: 71 percent / aq. NaOH / tetrahydrofuran / 4 h / 0 °C 2.1: thiourea / aq. ethanol 2.2: 92 percent / aq. NaOH / Heating | ||
Multi-step reaction with 2 steps 1: 63 percent / PBr3; pyridine 2: 64.3 percent / thiourea; aq. KOH / ethanol |
Multi-step reaction with 2 steps 1: 75 percent / SOCl2 / Heating 2: 1.) thiourea, 2.) KOH / 1.) 90percent ethanol, reflux, 5 h, 2.) water, reflux, 3 h | ||
Multi-step reaction with 3 steps 1: potassium hydroxide / dichloromethane / 3 h / 0 - 10 °C 2: sodium iodide / acetone / 18 h / 60 °C 3: hydrogenchloride / methanol; water / 3 h / 120 °C / Inert atmosphere | ||
Stage #1: 2,2'-[1,2-ethanediylbis(oxy)]bisethanol With p-toluenesulfonyl chloride; sodium hydroxide In tetrahydrofuran Stage #2: With thiourea In ethanol for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium carbonate In methanol; water at 50℃; for 20h; Inert atmosphere; | General procedure for the connection of dithiol to β-cyclodextrin (GP1) General procedure: Tosyl cyclodextrin 1 (300 mg, 0.23 mmol) was suspended in a mixture of methanol (15 mL), water (15 mL),and sodium carbonate (62 mg, 2.5 equiv) under an inert atmosphere. To remove dissolved oxygen, argon was bubbled through this mixture in advance (2 minutes), exposed to ultrasound (10 minutes) and bubbled by argon again (10 minutes). Then the dithiol (9.5 equiv) was added to the solution, which was then stirred under a condenser and an inert atmosphere at 50 °C for 20 hours. The reaction process was monitored by TLC (BuOH/EtOH/H2O 5/4/4,detection by H2SO4). After cooling to room temperature, the reaction mixture was neutralized by addition of hydrochloric acid (5% aqueous solution). After dilution of the reaction mixture to double volume by addition of water, unreacted dithiol was removed by extraction with chloroform (3 × 1:1). The solvents of the water layer were evaporated under reduced pressure. The solid residue was adsorbed on silica gel (10 × weight of the residue) and purified by column chromatography on silica gel (200 × weight of the residue). |
19.7% | With sodium carbonate In ethanol at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With potassium hydroxide; Aliquat 336; 4-methoxy-phenol In chloroform for 0.25h; | |
1.3 g | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -5 - 20℃; for 3h; | 6 Example 6 Discrete Thio Ester To 6.6 mL (40 mmol) 2,2′-(ethylenedioxy)dimethanethiol in 200 mL of tetrahydrofuran (THF) was added 20.9 mL of diisopropylethyl amine and the resulting dry solution was added to 11.5 mL of methacryloyl chloride (120 mmol) in 200 mL of dry THF, at -5° C., with good stirring over 1 hr. The reaction mixture was stirred at 0° C. for 1 hr and at 20° C. for one hour at which point 10 mL of isopropyl alcohol was added and the solvent was removed in vacuo. [0083] The residue was applied to a 330 g silica (gold) column in a minimum volume of chloroform and the column was eluted with 0-5% isopropyl alcohol in methylene chloride at 200 mL/min. The fraction which eluted at 13-14 min as a single peak was isolated as 1.3 g of yellow oil. AIBN initiated reaction of 50 mg of this material displayed a hard pellet. |
1.3 g | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -5 - 20℃; for 3h; | 6 Dithio Ester Example 6 Dithio Ester To 6.6 mL (40 mmol) of 2,2'-(ethylenedioxy)ethanedithiol in 200 mL of tetrahydrofuran (THF) was added 20.9 mL of diisopropylethyl amine and the resulting dry solution was added to 11.5 mL of methacryloyl chloride (120 mmol) in 200 mL of dry THF, at -5° C., with good stirring over 1 hr. The reaction mixture was stirred at 0° C. for 1 hr and at 20° C. for 1 hr at which point 10 mL of isopropyl alcohol was added and the solvent was removed in vacuo. The residue was applied to a 330 g silica (gold) column in a minimum volume of chloroform and the column was eluted with 0-5% isopropyl alcohol in methylene chloride at 200 mL/min. The fraction which eluted at 13-14 minutes as a single peak was isolated as 1.3 g of yellow oil. AIBN initiated reaction of 50 mg of this material displayed a hard pellet. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate In acetonitrile Heating; | |
40% | With potassium carbonate In acetonitrile Heating; | |
40% | Stage #1: 3,6-dioxa-1,8-octandithiol With potassium carbonate In acetonitrile for 1h; Reflux; Stage #2: N,N-bis<2-<(methylsulfonyl)oxy>ethyl>aniline In acetonitrile |
36% | Stage #1: 3,6-dioxa-1,8-octandithiol With potassium carbonate In acetonitrile at 80℃; Stage #2: N,N-bis<2-<(methylsulfonyl)oxy>ethyl>aniline In acetonitrile for 24h; | |
28.4% | Stage #1: 3,6-dioxa-1,8-octandithiol With potassium carbonate In acetonitrile at 80℃; Stage #2: N,N-bis<2-<(methylsulfonyl)oxy>ethyl>aniline In acetonitrile at 80℃; for 17h; | 1,4-Dioxa-7,13-dithia-10-phenyl-10-azacyclopentadecane (2) 3,6-Dioxa-1,8-octanedithiol (9.00 g, 49.37 mmol) was dissolved in 300 mL of dry MeCN, followed by addition of K2CO3 (15.00 g, 108.53 mmol). This suspension was stirred and heated up to 80 °C. Then, 1 (18.54 g, 55.18 mmol) dissolved in 150 mL dry MeCN, was added dropwise for 5 h. After another 12 h, the reaction mixture was cooled down to room temperature, white precipitate was filtered off, and the solvent evaporated in vacuo. The crude residue was chromatographed on silica gel with CHCl3, yielding 2 as a white crystalline solid (1.56 g, 28.4%, Rf = 0.84 with CHCl3/MeOH mixture (9:1)). 1H NMR (400 MHz, CDCl3): δ = 2.74-2.77 (t, 4H, -CH2S), 2.87-2.91 (t, 4H, -CH2S), 3.60-3.65 (m, 8H, -CH2N, -CH2O), 3.78-3.82 (t, 4H, -CH2O), 6.63-6.70 (m, 3H, ArH), 7.19-7.24 (t, 2H, ArH). |
Stage #1: 3,6-dioxa-1,8-octandithiol With potassium carbonate Stage #2: N,N-bis<2-<(methylsulfonyl)oxy>ethyl>aniline |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate In ethanol; water Heating; | |
62% | With sodium carbonate In ethanol; water for 20h; Reflux; | Formyl derivative of benzodithiacrownether. To a mixture of Na2CO3 (21.2 mmol) ina mixture of EtOH-H2O (1 : 1, 200 mL) at 75-85 and stirring 3,4-bis(2-chloroethoxy)benzaldehyde (4.24 mmol) and 3,6-dioxa-1,8-octanedithiol (4.66 mmol) in 10 mL of solventeach were added simultaneously for 1 h. The reaction mixture was heated to refl ux for 20 h, evaporated, 100 mL of water was added to the residue, and extracted with a mixture of benzene-chloroform (10 : 1). The extracts were evaporated in vacuo, theresidue was chromatographed on a silica gel column (Kieselgel 60, 0.063-0.100 mm, Merck), eluting successively with benzene and a mixture of benzene-ethyl acetate (20 : 1). The product was a light yellow powder, yield 62%, m.p. 130-131 °C (compare Ref. 17: m.p. 130-132 °C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With thiourea In ethanol for 3h; Reflux; | 3 Crosslinker (Compound 2 in the above synthetic route) Dissolve 1,2-bis(2-bromoethoxy)ethane (304mg, 1.0mmol) and thiourea (365.8mg, 4.8mmol) in 95% ethanol (30mL).The reaction mixture was stirred at reflux for 3h, then 1M sodium hydroxide solution (20-20mL) was added and refluxing continued for 2h.Separate and acidify the aqueous layer with 2.0M dilute hydrochloric acid (pH=1), and then extract the acidic solution with petroleum ether (3×30 mL).Mixing the organic phase, washed with brine, dried over anhydrous MgS04. 4dried.The solvent was removed under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 2 as a colorless oil (156 mg, 85.7%). |
64.3% | With potassium hydroxide; thiourea In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: triethylene glycol di-(p-toluenesulfonate) With thiourea In ethanol Stage #2: With sodium hydroxide Heating; | |
Multi-step reaction with 2 steps 1: sodium iodide / acetone / 18 h / 60 °C 2: hydrogenchloride / methanol; water / 3 h / 120 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With cerium (III) carbonate In N,N-dimethyl-formamide at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With oxygen In N,N-dimethyl-formamide for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With caesium carbonate In tetrahydrofuran for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate In tetrahydrofuran for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In ethanol at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In methanol at 29℃; for 20h; UV-irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With caesium carbonate In N,N-dimethyl-formamide at 45 - 50℃; for 60h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate In ethanol; water at 60℃; for 20h; | |
With caesium carbonate In ethanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 40 percent / K2CO3 / acetonitrile / Heating 2: 80 percent / NaNO2; HCl / H2O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With pyridine In N,N-dimethyl-formamide at 20℃; for 0.5h; | 1 g (5.5 mmol) 3,6-Dioxaoctane-l,8-dithiol was dissolved in 10 ml DMF and 1 g (3.6 TΠTΠOI) tritylchlorid and 1 ml pyridine were added. The solution was stirred at room temperature for 30 min and mono-S-trityl protected 3,6-dioxaoctane-l ,8-dithiol was purified by RP-HPLC (yield 850 mg, 2 mmol, 56 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium carbonate In ethanol; water for 48h; Heating; | |
52% | With caesium carbonate In acetonitrile for 78h; Reflux; | Benzothiacrown Ethers 3c-f and Benzothiacrown Naphthalimides 5c-f General procedure: To a suspension of Cs2CO3 (1.10 mmol) and dichloride 1a or 5g (or diiodide 1b, 5h for compounds 3c and 5c, respectively) (0.30 mmol) in MeCN (30 mL) was added a solution of dithiol 2c-f (0.33 mmol) in MeCN (30 mL) dropwise under stirring. The reaction mixture was heated and refluxed for 78 h. Then, it was concentrated in vacuo. H2O (150 mL) was added to the residue, and the mixture was extracted with CHCl3 (compounds 5c-f were washed with H2O). The extracts were concentrated in vacuo, and the residue was purified by silica gel column chromatography with eluent benzene-EtOAc (for 3c-f) or benzene-EtOH (gradient) (for 5c-f). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With trifluoroacetic acid In dichloromethane; benzene 48 qqqqqqqqqqqqqqqwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww; wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww; | |
93% | With trifluoroacetic acid In dichloromethane; benzene simultaneous dropwise addn. of 1,1'-bis(α-hydroxyalkyl)ferrocene (soln. in 1:1 CH2Cl2-C6H6) and dithiol (soln. in CH2Cl2) by stirring, refluxing with few drops CF3COOH for ca 48 h, washing with aq. NH3, water,dried over MgSO4; evaporating, chromy. (column, then TLC), elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With Et3N In tetrahydrofuran under dry N2, Schlenk flask; mixt. of Fe complex, ligand and Et3N was stirred at room temp. for 0.5 h to give intermediate salt (IR), CS2 was added, stirring for 0.5 h at room temp., then (BrCH2)2C6H4 was added, stirring for 12 h at room temp.; solvent was removed, residue was chromd.; IR, NMR; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: diethylene glycol divinyl ether; 3,6-dioxa-1,8-octandithiol With azobis(2-cyanobutane) at 50 - 70℃; for 2h; Stage #2: Allyl glycidyl ether With azobis(2-cyanobutane) at 70℃; for 37h; | 1 253.4 g (1.39 mole) of dimercaptodioxaoctane (DMDO) was added to a 1 liter 4-neck flask under a nitrogen atmosphere. While stirring, the contents of the flask were heated to 50°C, and 146.6 g (0.93 mole) of diethylene glycol divinyl ether (DEG-DVE) was added over 1 hr. The temperature of the reaction mixture was increased to 70°C and 0.05 g of free-radical initiator VAZO 67 (2,2'-azobis (2- methylbutyronitrile), Du Pont) was added. The temperature of the reaction mixture was maintained at 70°C for an additional hour. Completion of the reaction of DEG- DVE with DMDO was indicated by a mercaptan equivalent value of 420. Allyl glycidyl ether (AGE) (110. 87 g, 0.97 mole, 2% stoichiometric excess) was added at 70°C over 1 hr and the reaction mixture was heated at 70°C for an additional hour. Ten portions OF VAZO°67 (0.165 g each) were then added at 3 hr intervals at 70°C. Following addition OF VAZO°67 the reaction mixture was heated at 70°C for 5 hr. The reaction mixture was then degassed at 70°C/4-5 mm Hg for 3 hr to provide a liquid epoxy-capped polythioether having a faint yellow color, a viscosity of 5.0 poise, and an epoxy equivalent value of 563. The reaction yield was 508.7 G (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: diethylene glycol divinyl ether; 3,6-dioxa-1,8-octandithiol With azobis(2-cyanobutane) at 60 - 70℃; for 10.8333h; Stage #2: Allyl glycidyl ether With azobis(2-cyanobutane) at 70℃; for 42h; | 2 62.17 g (moles) of DMDO was added to a 250 ml 3-neck flask under a nitrogen atmosphere. While stirring, DMDO was heated to 60°C and 44.88 g (mole) of DEG-DVE was added to the reaction mixture over a period of 50 minutes while the temperature of the reaction was maintained at 60°C-70°C. The reaction mixture was heated at 70°C for an additional 4 hr. Two portions OF VAZO°67 (0.036 g each) were added to the reaction mixture at 1.5 hr intervals and heated at 70°C for 1.5 hr. The mercaptan equivalent value of the reaction mixture was 890. An additional portion of VAZO 67 (0.036 G) was added and the reaction mixture heated for another 1.5 hr. A mercaptan equivalent value of 893 indicated completion of the reaction of DEG-DVE with DMDO. AGE (13.21 g, 0.116 mole, 2% stoichiometric excess) was added at 70° in one portion and the reaction mixture was heated for 2 hr. Eight portions of VAZO 67 (0.035 g each) were added at 3 hr intervals at 70°C and heating was continued for another 4 HR. At this stage, the mercaptan equivalent value of the reaction mixture was of 28,642. To complete the reaction, an additional 4.8 g (0.042 mole, 38% stoichiometric excess) of AGE was added and the reaction mixture was heated for 1 lu at 70°C. Two portions OF VAZO°67 (0.036 g each) were added at 3 hr intervals. Following the addition OF VAZO°67, the reaction mixture was heated at 70°C for 5 hours. The reaction mixture was then degassed at 70°C/4-5 mm Hg for 2 hr to provide a slightly hazy, liquid epoxy-capped polythioether having a faint yellow color, a viscosity of 26 poise, and an epoxy equivalent value of 1,217. The reaction yield was 120.0 g (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With caesium carbonate In N,N-dimethyl-formamide at 45 - 50℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate In acetonitrile at 80℃; for 29h; Inert atmosphere; | 1,4-Dioxa-7,13-dithia-10-(3-methoxyphenyl)-10-azacyclopentadecane (3) To a stirred solution of 3-methoxy-bis[N,N-(2-hydroxyethyl)]aniline (4.20 g, 19.92 mmol) and EtOAc (150 mL) in an ice-water bath, methanesulfonyl chloride (6.85 g, 59.77 mmol) was slowly added, then triethylamine (8.06 g, 79.69 mmol) in 20 mL EtOAc was added dropwise during 30 min. The reaction was stirred for further 15 min at room temperature. The precipitate was filtered off and washed with 100 mL EtOAc. The combined filtrates were washed with water (80 mL×3), then, dried over anhydrous Na2SO4. The solvent was evaporated in vacuum and the residue (7.09 g, yield 97%) was obtained. To a stirred solution of 3,6-dioxa-1,8-octanedithiol (0.99 g, 5.45 mmol), anhydrous MeCN (80 mL) and K2CO3 (2.26 g, 16.35 mmol) at 80 °C under nitrogen atmosphere, the above residue (2.00 g, 5.45 mmol) in 50 mL dry MeCN was added dropwise during 5 h. The reaction was refluxed for 24 h. The precipitation was discarded after filtration and the solvent was removed by evaporation. The crude residue was purified by chromatography on silica gel eluting with petroleum ether/ethyl acetate (1:3). 3 was obtained as a white powder (0.69 g, 35%), m.p.: 59.3-60.7 oC.. 1H NMR (CDCl3, 300 MHz): δ (ppm): 2.76 (t, J = 5.0 Hz, 4H), 2.89 (t, J =8.1 Hz, 4H), 3.59-3.64 (m, 8H), 3.78-3.82 (m, 7H), 6.20 (s, 1H), 6.25-6.28 (m, 2H), 7.13 (t, J = 8.2 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ (ppm): 29.9, 31.5, 52.4, 55.6, 71.1, 74.7, 98.9, 101.2, 105.4, 130.6 148.6, 161.4. HRMS (EI-TOF): m/z calcd for C17H27NO3S2: 357.1432, found: 357.1429. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With sodium ethanolate In ethanol at 50℃; for 12h; Inert atmosphere; | 4.3. General procedure for preparation of compounds 19-24 (method B) General procedure: A dithiol (0.12 mmol) was dissolved in a sodium ethoxide solution in ethanol (0.01 M, 15 mL). This solution was added dropwise during 1 h to a solution of epoxide 1 (50 mg, 0.255 mmol) in dry ethanol (1 mL) at room temperature in an argon atmosphere. The reaction mixture was stirred at 22-78 °C for 2-24 h (refPreviewPlaceHolderTable 1) until complete conversion of the epoxide as monitored by TLC (silica gel; EtOAc/CH3OH/NH4OH 10:1:0.5). The solvent was removed on a rotary evaporator. The product was isolated by column chromatography or crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With samarium(III) chloride hexahydrate In chloroform at 60℃; for 1.5h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium In tetrahydrofuran; methanol at 20 - 60℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: Allyl glycidyl ether; 3,6-dioxa-1,8-octandithiol With 2,2'-azobis(isobutyronitrile) In N,N-dimethyl-formamide at 60℃; for 8h; Inert atmosphere; Stage #2: carbon dioxide With lithium bromide In N,N-dimethyl-formamide at 80℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 2,2'-azobis(isobutyronitrile) In N,N-dimethyl-formamide at 70℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 93% 2: 7% | With 2,2'-azobis(isobutyronitrile) In N,N-dimethyl-formamide at 60℃; for 8h; Inert atmosphere; Overall yield = 92 %; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,6-dioxa-1,8-octandithiol; triallyl cyanurate at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With azobis(2-cyanobutane) at 70℃; for 8h; | 1 Example 1 Synthesis of Tri-functional Sulfur- Containing Epoxy Example 1 Synthesis of Tri-functional Sulfur- Containing Epoxy [0128] In a 300 mL, 3 -necked round bottom flask fitted with a thermal probe, mechanical stirrer, and nitrogen (N2) inlet, 18.8 g of triallyl cyanurate (TAC) and 41.91 g of l,8-dimercapto-3,6-dioxaoctane (DMDO) were charged, and the mixture was stirred at room temperature for 20 minutes. The mixture was then heated to 70°C, and 16 mg of Vazo-67 (available from Dupont) was added. The reaction mixture was maintained at 70°C for 8 hours. The progress of the reaction was monitored by determining the mercaptan equivalent weight (MEW). The final MEW was 297, and the material had a viscosity of 20 poise at 25°C, spindle 6 at 50 RPM, measured using a CAP2000 viscometer. | |
Stage #1: 3,6-dioxa-1,8-octandithiol; triallyl cyanurate at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With azobis(2-cyanobutane) at 70℃; for 8h; Inert atmosphere; | 1 In a 300 mL, 3-necked, round-bottom flask fitted with a thermal probe, mechanical stirrer, and nitrogen (N2) inlet, 98 g (0.394 mol) of triallylcyanurate (TAC) and 215 g of 1,8-dimercapto-3,6-dioxaoctane (DMDO) were charged, and the mixture stirred at room temperature for 20 minutes. The mixture was then heated to 70°C, and 100 mg of Vazo-67(Dupont) was added. The reaction mixture was maintained at 70°C for 8 hours to provide thiol-terminated intermediate A. The progress of the reaction was monitored by determining the mercaptan equivalent weight (MEW). The final MEW was 297, and the material had a viscosity of 20 poise at 25°C, spindle 6 at 50 RPM, measured using a CAP2000 viscometer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol In water at 0.2℃; for 0.5h; Inert atmosphere; Stage #2: acetylacetone In ethanol; chloroform; water at 0.2℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 79% 2: 9% | Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol In ethanol; water at 20℃; for 0.333333h; Stage #2: ethanolamine In ethanol; water at 20℃; | 22 Preparation of 1,5,3-dithiazepanes 3a-e and macroheterocycles 4a-d, 5a-f, 6a-d and 10a,b General procedure: Dithiol 2a-e or 9a,b (1 mmol) was mixed with a 37 % solution of formaldehyde (0.15 mL, 2 mmol), and ethanol (3 mL) at room temperature over a period of 20 min. A solution of 0.07 g (1 mmol) of hydroxylamine hydrochloride 1a in water (3 mL) was added to the reaction mixture and the mixture was stirred for 3-4 h at room temperature. The product obtained from hydroxylamine hydrochloride was neutralized with a 10 % solution of NaOH. White precipitate that formed was filtered off and washed with H2O (3*15 mL) then dried. The corresponding amino alcohol 1b-e (1 mmol) in CHCl3 (15 mL) was added dropwise to the reaction mixture and the mixture was stirred for 3-4 h at room temperature. The water was removed and the solution was dried with anhydrous MgSO4. Solvent was removed, and the crude product was separated by column chromatography to give a pure sample 3a-e, 5a-f and 6a-d, which was analyzed by NMR spectroscopy. The precipitate that formed from dithiol 2b-e and hydroxylamine hydrochloride 1a was filtered off, then was washed with water and dried. The product was washed with CHCl3 and dried. The details of further purification performed for the new compounds are described in Product Data. 4.2.22. 2-[19-(2-Hydroxyethyl)-1,11,14,24-tetraoxa-4,8,17,21-tetrathia-6,19-diazacyclohexacosanyl]-1-ethanol (10a). Colourless oil, yield (0.21 g) 79%, Rf 0.68 (CH2Cl2/hexane/CH3CO2Et, 3:3:1); vmax (liquid film) 754 (-C-S-C-), 1040, 1110, 3444 cm-1; δH (400 MHz, CDCl3, 25 °C) 2.71 (8Н, s, SCH2CH2), 2.83 (4Н, t, NCH2CH2), 3.57 (8Н, s, NCH2S), 3.59 (8Н, t, OCH2CH2O), 3.62 (4Н, t, CH2, HOCH2), 4.08 (8Н, s, OCH2CH2S); δC (100 MHz, CDCl3) 31.0 (SCH2CH2), 54.0 (NCH2CH2), 57.5 (NCH2S), 59.3 (HOCH2), 70.2 (OCH2CH2S), 71.5 (OCH2CH2O); ESI (70 eV); m/z (%): 573 (9) [M+K]+, 557 (47) [M+Na]+, 290 (19) [M+2Na]2+, 268 (100) [M+2H]2+, 569 (100) [M+Сl]-. Anal. Calcd for С20Н42N2О6S4: С, 44.91; Н, 7.92; N, 5.24; S, 23.98. Found: С, 44.93; Н, 7.85; N, 5.19; S, 24.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate In acetonitrile for 16h; Reflux; | Dithia- and Diazacrown Derivatives 7a,b,8,12a,b; General Procedure General procedure: The procedure was adopted from the literature.22 To a suspension of Cs2CO3 (2.5 mmol) in anhydrous MeCN (100 mL) was added dropwise simultaneously two 25 mL solutions in MeCN, each containing the appropriate chromene (0.5 mmol) and thiol or amine (1.05 mmol). The mixture was refluxed for 16 h. Upon cooling, the precipitate was filtered off and washed with MeCN (20 mL). The combined organic fractions were evaporated and the residue was dissolved in CH2Cl2 (50 mL). The resulting solution was washed with H2O (50 mL) and evaporated in the presence of a small amount of benzene. The residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With caesium carbonate In acetonitrile for 16h; Reflux; | Dithia- and Diazacrown Derivatives 7a,b,8,12a,b; General Procedure General procedure: The procedure was adopted from the literature.22 To a suspension of Cs2CO3 (2.5 mmol) in anhydrous MeCN (100 mL) was added dropwise simultaneously two 25 mL solutions in MeCN, each containing the appropriate chromene (0.5 mmol) and thiol or amine (1.05 mmol). The mixture was refluxed for 16 h. Upon cooling, the precipitate was filtered off and washed with MeCN (20 mL). The combined organic fractions were evaporated and the residue was dissolved in CH2Cl2 (50 mL). The resulting solution was washed with H2O (50 mL) and evaporated in the presence of a small amount of benzene. The residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: N,N-bis(methoxymethyl)-N-(m-fluorophenyl)amine With copper(l) chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-octandithiol at 20℃; for 5h; Inert atmosphere; | 4.3 Cycloaminomethylation of 3,6-dioxa-1,8-octanedithiol with N,N-bis(methoxymethyl)-N-arylamines General procedure: General procedure. N,N-Bis(methoxymethyl)-N-arylamine (1.00 mmol) obtained in situ by a reported procedure,25 the solvent (10 mL), and CuCl (0.05 mol) were stirred under argon for 30 min at room temperature, then 3,6-dioxa-1,8-octanedithiole (1.00 mmol) in 1 mL of the solvent was added. The reaction mixture was stirred at 20 °C for 5 h and concentrated, and the residue was chromatographed on a column with SiO2 to isolate pure heterocyclic products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: N,N-bis(methoxymethyl)-N-(p-fluorophenyl)amine With copper(l) chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-octandithiol at 20℃; for 5h; Inert atmosphere; | 4.3 Cycloaminomethylation of 3,6-dioxa-1,8-octanedithiol with N,N-bis(methoxymethyl)-N-arylamines General procedure: General procedure. N,N-Bis(methoxymethyl)-N-arylamine (1.00 mmol) obtained in situ by a reported procedure,25 the solvent (10 mL), and CuCl (0.05 mol) were stirred under argon for 30 min at room temperature, then 3,6-dioxa-1,8-octanedithiole (1.00 mmol) in 1 mL of the solvent was added. The reaction mixture was stirred at 20 °C for 5 h and concentrated, and the residue was chromatographed on a column with SiO2 to isolate pure heterocyclic products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: N,N-bis(methoxymethyl)-N-(m-chlorophenyl)amine With copper(l) chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-octandithiol at 20℃; for 5h; Inert atmosphere; | 4.3 Cycloaminomethylation of 3,6-dioxa-1,8-octanedithiol with N,N-bis(methoxymethyl)-N-arylamines General procedure: General procedure. N,N-Bis(methoxymethyl)-N-arylamine (1.00 mmol) obtained in situ by a reported procedure,25 the solvent (10 mL), and CuCl (0.05 mol) were stirred under argon for 30 min at room temperature, then 3,6-dioxa-1,8-octanedithiole (1.00 mmol) in 1 mL of the solvent was added. The reaction mixture was stirred at 20 °C for 5 h and concentrated, and the residue was chromatographed on a column with SiO2 to isolate pure heterocyclic products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: N,N-bis(methoxymethyl)-N-(p-chlorophenyl)amine With copper(l) chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-octandithiol at 20℃; for 5h; Inert atmosphere; | 4.3 Cycloaminomethylation of 3,6-dioxa-1,8-octanedithiol with N,N-bis(methoxymethyl)-N-arylamines General procedure: General procedure. N,N-Bis(methoxymethyl)-N-arylamine (1.00 mmol) obtained in situ by a reported procedure,25 the solvent (10 mL), and CuCl (0.05 mol) were stirred under argon for 30 min at room temperature, then 3,6-dioxa-1,8-octanedithiole (1.00 mmol) in 1 mL of the solvent was added. The reaction mixture was stirred at 20 °C for 5 h and concentrated, and the residue was chromatographed on a column with SiO2 to isolate pure heterocyclic products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: N,N-bis(methoxymethyl)-N-(m-bromophenyl)amine With copper(l) chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-octandithiol at 20℃; for 5h; Inert atmosphere; | 4.3 Cycloaminomethylation of 3,6-dioxa-1,8-octanedithiol with N,N-bis(methoxymethyl)-N-arylamines General procedure: General procedure. N,N-Bis(methoxymethyl)-N-arylamine (1.00 mmol) obtained in situ by a reported procedure,25 the solvent (10 mL), and CuCl (0.05 mol) were stirred under argon for 30 min at room temperature, then 3,6-dioxa-1,8-octanedithiole (1.00 mmol) in 1 mL of the solvent was added. The reaction mixture was stirred at 20 °C for 5 h and concentrated, and the residue was chromatographed on a column with SiO2 to isolate pure heterocyclic products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: N,N-bis(methoxymethyl)-N-(p-bromophenyl)amine With copper(l) chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-octandithiol at 20℃; for 5h; Inert atmosphere; | 4.3 Cycloaminomethylation of 3,6-dioxa-1,8-octanedithiol with N,N-bis(methoxymethyl)-N-arylamines General procedure: General procedure. N,N-Bis(methoxymethyl)-N-arylamine (1.00 mmol) obtained in situ by a reported procedure,25 the solvent (10 mL), and CuCl (0.05 mol) were stirred under argon for 30 min at room temperature, then 3,6-dioxa-1,8-octanedithiole (1.00 mmol) in 1 mL of the solvent was added. The reaction mixture was stirred at 20 °C for 5 h and concentrated, and the residue was chromatographed on a column with SiO2 to isolate pure heterocyclic products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 15 Example 15 Tetra Thioester Crosslinker To a 500 mL 3-neck round bottom flask under Argon chilled at 0° C., 100 mL of dry THF was added. Under stirring, 20 g (0.11 mmol) of 2,2′-(ethylenedioxy)diehanthiol and 16 mL (0.09 mol) of diisopropylethylamine were added. To 40 mL of dry THF, 5 mL (0.045 mol) of succinyl chloride was dissolved. Under Argon, the solution was added drop wise into the reaction mixture at 0° C. via an addition funnel with vigorous stirring. Following the addition, the reaction mixture was stirred for 1 hour at 0° C. and then allowed to warm up to room temperature to stir overnight. The reaction mixture was then concentrated under vacuum. Flash chromatography with ethyl acetate in DCM from 0% to 15% at 254 nm gave the dithiol ester intermediate. | |
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 15 Tetra Thioester Crosslinker Example 15 Tetra Thioester Crosslinker To a 500 mL 3-neck round bottom flask under argon chilled at 0° C., 100 mL of dry THF was added. Under stirring, 20 g (0.11 mol) of 2,2'-(ethylenedioxy)ethanthiol and 16 mL (0.09 mol) of diisopropylethylamine were added. To 40 mL of dry THF, 5 mL (0.045 mol) of succinyl chloride was dissolved. Under argon, the solution was added drop wise into the reaction mixture at 0° C. via an addition funnel with vigorous stirring. Following the addition, the reaction mixture was stirred for 1 hr at 0° C. and then allowed to warm up to room temperature to stir overnight. The reaction mixture was then chilled on ice to precipitate the amine salt. The white precipitate was removed by filtering through a medium fritted glass filter and washed with ice cold THF. The filtrate was collected and concentrated under vacuum. Flash chromatography with ethyl acetate in DCM from 0% to 15% at 254 nm gave the dithiol ester intermediate. To a 250 mL 3-neck round bottom flask under argon chilled at 0° C., 50 mL of dry THF was added. Under stirring, 3.17 g (7.1 mmol) of dithiol ester intermediate and 3.6 mL (20 mmol) of diisopropylethylamine were added. To 50 mL of dry THF, 2 mL (20 mmol) of methacryloyl chloride was dissolved. Under argon, the solution was added drop wise into the reaction mixture at 0° C. via an addition funnel with vigorous stirring. Following the addition, the reaction mixture was stirred for 1 hr at 0° C. and then allowed to warm up to room temperature to stir overnight. The reaction mixture was then chilled on ice to precipitate the amine salt. The white precipitate was removed by filtering through a medium fritted glass filter and washed with ice cold THF. The filtrate was collected and concentrated under vacuum. Flash chromatography with ethyl acetate in dichloromethane from 0% to 10% at 254 nm eluted the desired tetra thiol ester crosslinker from 4 min to 12 min. The mass spectrometry analysis gave 605.1 corresponding to [M+Na]+ of the calculated mass of C24H38O8S4. | |
3.93 g | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; | 10 Synthesis of dithioester 11: An oven-dried 250 mL 3-neck round bottom flask was fitted with a stir bar and a 100 mL addition funnel. To this flask was added 3,6-dioxaoctane-1,8-dithiol (20.0 g, 110 mmol), THF (100 mL), and diisopropylamine (DIEA) (15.8 mL, 90.0 mmol) sequentially. The flask was cooled in 0° C. ice bath. Then succinyl chloride (5.0 mL, 45.0 mL) and THF (40 mL) were added to the funnel. The succinyl chloride solution was added dropwise into the reaction mixture, which was stirred overnight. To work up, the brown solution with white precipitate was filtered over a medium-porosity glass fritted funnel. The filtrate was passed through a silica gel plug. The filtrate was concentrated under reduced pressure to give a brown syrup, which was first dissolved in 100 mL DCM. Using gentle swirling, the DCM fraction was washed with 0.1 M NaHCO3 (100 mL) and saturated NaCl solution (100 mL). The DCM fraction was dried over Na2SO4, and the solvent was removed under reduced pressure to give a red liquid (29.65 g). The liquid can be decolorized with activated charcoal, before being separated on a flash column to give 11 as an oily liquid (3.93 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In acetone at 20℃; for 0.25h; | |
With triethylamine In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium hydroxide In ethanol; toluene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 3,6-dioxa-1,8-octandithiol With triethylamine In methanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: S-(+)-2-methyl-N-p-tosylaziridine In methanol at 20 - 35℃; for 5h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With hydrogenchloride In methanol; water at 120℃; for 3h; Inert atmosphere; | General procedure for deacetylation of bis(thioacetylated) oligo ethylene glycols (GP5) General procedure: Compounds 4a-c were prepared by a modified procedure known from the literature3. Bis(thioacetylated) oligoethylene glycol 3a, 3b or 3c (3.1 mmol) was dissolved in a mixture of methanol (5 mL), water (5 mL) and hydrochloric acid (0.8 mL, 9 mmol, 3 equiv). Argon was bubbled through the mixture of methanol, water and acid in advance (2minutes), exposed to ultrasound (10 minutes) and argon was bubbled through by again (10 minutes) to remove all dissolved oxygen. The reaction mixture was then heated to 120 °C under a reflux condenser and inert atmosphere for 3 hours. The reaction process was monitored by TLC (detection by KMnO4). After cooling to room temperature,the reaction mixture was diluted to the double volume by addition of water and extracted with chloroform (3 × 1:1). The organic layers were collected and concentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (150 × weight of the residue). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; trans-[platinum(IV)dichloride(ethylenediamine)(N-(2-hydroxyethyl)ethylenediamine)] dichloride monohydrate; sodium perchlorate; sodium acetate; acetic acid; disodium ethylenediamine tetraacetic acid; sodium chloride In water at 25℃; for 1h; | General procedure: For kinetic runs, solutions of trans-[PtCl2(en)(heda)]2+ and the appropriate dithiol were prepared by adding the required amount of each stock solution to a specific buffer solution, respectively. These solutions were flushed with nitrogen for 10 min and then loaded onto the stopped-flow machine. Reactions were initiated by mixing equal volumes of trans-[PtCl2(en)(heda)]2+ and the dithiol solutions directly in the stopped-flow machine under pseudo first order conditions, with the concentration of dithiol being at least tenfold greater than that of trans-[PtCl2(en)(heda)]2+. Time-resolved spectra for the reactions between trans-[PtCl2(en)(heda)]2+ (0.1 mM) and the dithiols (1.0 mM) in buffer solutions were also obtained using the stopped-flow machine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In water at 20℃; for 3h; | 1,6,9-Trioxa-3,12-dithiacyclotridecane (1). 1,6,9-Trioxa-3,12-dithiacyclotridecane (1). A mixture of 6 mL of 37% aqueous formaldehyde and 3.2 mL of 3,6-dioxaoctane-1,8-dithiol was stirred for 3 h at 20°C. The mixture was extracted with chloro-form, and the extract was evaporated. Yield 1.9 g (86%), nD20 = 1.5244, Rf 0.45. 1H NMR spectrum (CDCl3), δ, ppm: 2.77 t (4H, 4-H, 11-H, J = 5.6 Hz), 3.62 br.s (4H, 7-H, 8-H), 3.64 t (4H, 5-H, 10-H, J = 5.6 Hz), 4.65 br.s (4H, 2-H, 13-H). 13C NMR spectrum (CDCl3), δC, ppm: 32.7 (C4, C11), 67.4 (C2, C13), 69.7 (C7, C8), 72.0 (C5, C10). Found, %: C 42.80; H 7.16; S 28.52. C8H16O3S2. Calculated, %: C 42.83; H 7.19; S 28.59. |
86% | In water at 20℃; for 3h; | 4.2.1. 1,6,9-Trioxa-3,12-dithiacyclotridecane (9) A mixture of a 37% aqueous formalin solution (6 mL, 2 mol) and 3,6-dioxa-1,8-octanedithiol (3.2 mL, 1 mol) was stirred at 20 °C for 3 h and extracted with CHCl3. The extract was evaporated, and 1,6,9-trioxa-3,12-dithiacyclotridecane (9) was isolated. Yield 1.9 g (86%), colorless oil, Rf 0.45; nD 1.5244; nmax (liquid film) 2914-2868 (br), 1404, 1287, 1103, 1018, 709, 656 cm-1; δH (500.17 MHz, CDCl3) 2.77 (4H, t, J 5.6 Hz, H-4,11), 3.62 (4H, br. s, H-7,8), 3.64 (4H, t, J 5.6 Hz, H-5,10), 4.65 (4H, br. s, H-2,13); δC (125.78 MHz, CDCl3) 32.7 (C-4, C-11), 67.4 (C-2, C-13), 69.7 (C-7, C-8), 72.0 (C-5, C-10). Anal. Calcd. (%) for C8H16O3S2: C, 42.83; H, 7.18; S, 28.59; found: C, 42.80; H, 7.16; S, 28.52. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium carbonate In ethanol at 20℃; | 2,2’,3,3’-bis-(2,2’-(ethylenedioxy)diethanthio)-1,4-dione (7) To a solution of p-chloranil (1a) (1 g, 4.066 mmol) in ethanol (30 mL) with Na2CO3 (1.56 g) was added 2,2’-(ethylenedioxy)diethanthiol (6) (1.48 gr, 8.007 mmol) and stirred for2-3 h at room temperature. The colour of the solution quickly changed and the reaction was monitored by TLC. Chloroform (30 mL) was added to the reaction mixture. The organic layer was washed with water (4 × 30 mL), and dried over Na2SO4. After the solvent was evaporated the residue was purified by column chromatography on silica gel. yield: 1.9589 g (% 52); Red Oil. Rf= 0.35 (CHCl3). IR(KBr): 2966, 2894, 2860, 2819 (C-H), 1660 (C=O), 1583 (C=C) cm-1. 1H-NMR (499.74 MHz, CDCl3): δ = 3.17-3.80 (m, 8H, -SCH2), 4.13- 4.16 (m, 16H, -O-CH2). 13C-NMR (125.66 MHz, CDCl3): δ = 29.39, 33.55, 37.77, 39.90 (-S-CH2), 167.17, 68.59, 69.46, 69.73 (-O-CH2), 27.81, 129.82, 131.49, 147.66 (Carom); 175.31 (C=Oquinone). MS (+ESI): m/z 465 [M]+. Anal. Calcd for C18H24O6S4 (M, 464.6): C, 46.53; H, 5.21 ; S, 27.60 . Found C, 46.91; H, 5.69 ; S, 28.22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In methanol at 65℃; for 1h; | 2 Synthesis of 2,4-diamino-6- (2- {2- [2- (2-mercaptoethoxy) ethoxy] ethylthio} ethyl) -1,3,5-triazine In a 100 mL flask equipped with a thermometer, 6.86 g (20.0 mmol) of 2,4-diamino-6-vinyl-1,3,5-triazine,22.6 g (100.0 mmol) of 1,2-bis (2-mercaptoethoxy) ethane and 20 mL of methanol were charged to prepare a reaction solution.The reaction was allowed to proceed at 65 ° C. for 1 hour while stirring,After concentrating the reaction solution under reduced pressure, 50 mL of toluene was added,And the mixture was stirred at room temperature for 30 minutes.The lower layer was extracted by liquid separation operation and concentrated under reduced pressure,6.07 g of transparent liquid (yield 95%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In water at 20℃; for 0.75h; Sonication; | Sulfur-Containing Bis-epoxides 3d-f; General Procedure General procedure: To a solution of (±)-epichlorohydrin (30 mmol, 3.0 g), sodium hydroxide (30 mmol, 1.3 g) and water (1 mL), tetrabutylammonium hydrosulfate (0.62 mmol, 0.2 g) and the corresponding dithiol 1d-f (5.5 mmol) were added. The reaction was stirred for 45 min at r.t. in an ultrasonic bath. The reaction mixture was filtered and washed with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate and then the solvent was removed. The residue was purified by flash chromatography (silica gel, EtOAc) and bisepoxides 3d-f were obtained as pale-yellow oils. |
With sodium hydroxide In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 1.5h; Inert atmosphere; | E1 Example E1 Synthesis of Linker (L1) Example E1 Synthesis of Linker (L1) (0339) (0340) A 1 l three-neck flask was equipped with pressure exchange, magnetic stirring bar and dropping funnel. The flask was loaded with 15.1 g of 2,2′-dithiodipyridine, 500 ml of methanol and 50 μl of N,N-diisopropylethylamine under inert atmosphere. A solution of 2-[2-(2-mercapto-ethoxy)-ethoxy]-ethanethiol in methanol (2 g/120 ml) was added drop-wise over a period of 30 min. 1 h after the ending of the first addition a second portion of the 2-[2-(2-mercapto-ethoxy)-ethoxy]-ethanethiol (0.5 g in 30 ml methanol) was added drop-wise and the reaction mixture was stirred at room temperature. (0341) After complete conversion of the disulfide, the solvent was removed at room temperature under reduced pressure. The residual oil (18.4 g) was purified by flash chromatography on silica (mobile phase: hexane/ethyl acetate 2:1 (v/v)). The crude product was further purified by a second chromatography on silica (mobile phase: hexane/ethyl acetate 1:1 (v/v)). L1 was obtained in 49% yield (2.7 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In toluene at 110℃; for 29h; Dean-Stark; | General Procedure for the preparation of Cyclic Stannathianes (1-4). General procedure: In a two-necked flask fitted with a Dean-Stark apparatus was placed dibutyltin oxide (5.0 g, 20 mmol) and toluene (80 mL), and the resulting suspension was heated to reflux. Subsequently, a solution of appropriate dithiol (i-iv) (20 mmol) in toluene (25 mL) was added dropwise with stirring to the refluxing reaction mixture during 5 h (see Scheme below). After the addition of reagent had been completed, the resulting mixture was refluxed for 24 h, cooled to ambient temperature, and then concentrated in vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With caesium carbonate In acetonitrile for 78h; Reflux; | Benzothiacrown Ethers 3c-f and Benzothiacrown Naphthalimides 5c-f General procedure: To a suspension of Cs2CO3 (1.10 mmol) and dichloride 1a or 5g (or diiodide 1b, 5h for compounds 3c and 5c, respectively) (0.30 mmol) in MeCN (30 mL) was added a solution of dithiol 2c-f (0.33 mmol) in MeCN (30 mL) dropwise under stirring. The reaction mixture was heated and refluxed for 78 h. Then, it was concentrated in vacuo. H2O (150 mL) was added to the residue, and the mixture was extracted with CHCl3 (compounds 5c-f were washed with H2O). The extracts were concentrated in vacuo, and the residue was purified by silica gel column chromatography with eluent benzene-EtOAc (for 3c-f) or benzene-EtOH (gradient) (for 5c-f). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol In water at 20℃; for 0.5h; Stage #2: L-leucine In water at 20℃; for 4h; | Oxathiazacycloalkanes. General method. General procedure: A mixture of 15 mmol of 3,6-dioxa-1,8-octanedithiol and 0.22 mL (30 mmol) of 37% aqueous solution of formaldehyde was stirred at room temperature for 30 min, 15 mmol of amino acid dissolved in 6 mL of water was added dropwise, and the mixture was stirred for 4 h at room temperature. Compounds 4a and 4b were isolated by evaporation of water in air, the obtained reaction product was washed with chloroform and dried in air. |
Yield | Reaction Conditions | Operation in experiment |
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45% | Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol In water at 20℃; for 0.5h; Stage #2: Phenylalanine In water at 20℃; for 4h; | Oxathiazacycloalkanes. General method. General procedure: A mixture of 15 mmol of 3,6-dioxa-1,8-octanedithiol and 0.22 mL (30 mmol) of 37% aqueous solution of formaldehyde was stirred at room temperature for 30 min, 15 mmol of amino acid dissolved in 6 mL of water was added dropwise, and the mixture was stirred for 4 h at room temperature. Compounds 4a and 4b were isolated by evaporation of water in air, the obtained reaction product was washed with chloroform and dried in air. |
Yield | Reaction Conditions | Operation in experiment |
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100% | With 2,2-dimethoxy-2-phenylacetophenone In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; UV-irradiation; |
Yield | Reaction Conditions | Operation in experiment |
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93% | Stage #1: pyridine; indium(III) nitrate hydrate In methanol for 0.25h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-octandithiol In methanol at 23℃; Inert atmosphere; | 4.2.1 [(SOOS)In(py)(NO3)] (1) Under a stream of dinitrogen, pyridine (0.528g, 6.68mmol) and In(NO3)3 (0.427g, 1.11mmol) were added to MeOH (15mL). After 15min, H2(SOOS) (0.200g, 1.10mmol) was added and the reaction mixture was left to stir for 19h. The solution was filtered and the filtrate was allowed to sit at -15°C. After 3d the reaction mixture was filtered to yield 4 as colourless crystals of (0.429g, 1.02mmol, 93%). Anal. Calc. for C11H17InN2O5S2: C, 30.29; H, 3.93; N, 6.42; S, 14.70. Found: C, 29.97; H, 3.87; N, 6.51; S, 13.82. M.p.=166-169°C. FT-IR (cm-1): 632m, 669s, 694m, 755m, 797 w, 811 w, 878 w, 932 w, 995 w, 994 w, 1026m, 1065 w, 1159 w, 1192 w, 1203 w, 1217 w, 1262m, 1275 w, 1345m, 1470s, 1603m, 2856 w, 2936 w. FT-Raman (cm-1): 120s, 140s, 214m, 284m, 340vs, 500vw, 649w, 671m, 1011s, 1037m, 1221w, 1278w, 1448w, 1603w, 2880w, 2940m, 3971w, 3071m. 1H NMR (dmso-d6, ppm): 3.57 (m, 12H, CH2), 7.37 (m, 2H, m-NC5H5), 7.77 (tt, JH-H=7.8, 2.0Hz, 1H, p-NC5H5), 8.55 (dd, JH-H=3.8, 1.6Hz, 2H o-NC5H5). 13C{1H} NMR (dmso-d6, ppm): 25.7 (SCH2), 66.2 (SCH2CH2O), 69.9 (OCH2CH2O), 123.6 (m-NC5H5), 135.8 (p-NC5H5), 149.2 (o-NC5H5). |
Yield | Reaction Conditions | Operation in experiment |
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99% | Stage #1: cycl-isopropylidene malonate; trimethyl orthoformate for 1h; Reflux; Stage #2: 3,6-dioxa-1,8-octandithiol for 2h; Reflux; | 16 Synthesis Example 16 Synthesis of compound represented by formula [35] 5,5 '- (5,8-dioxo-2,11-dithiadodecane-1,12-diylidene) bis (2,2-dimethyl-1 , 3-dioxane-4,6-dione) The Meldrum's acid [1] (13.6 g, 94.2 mmol) and trimethyl orthoformate [2] (134 g) were charged into a 200 mL four-necked flask and heated under reflux for 1 hour. Followed by the addition of 3,6-dioxa-1,8-octanedithiol [34] (7.8 g, 42.8 mmol) and heating under reflux for 2 hours. After completion of the reaction, the solvent was removed with an evaporator and dried to give 20.8 g of compound [35] (yield 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
500 g | Stage #1: 3,6-dioxa-1,8-octandithiol With sodium hydroxide In water at 60℃; Stage #2: Allyl glycidyl ether In water | 1 Synthesis of Hydroxyl-Containing Bis(alkenyl) ether Sodium hydroxide (108.06 g, 2.70 mol) was added to a flask containing deionized water (360 mL). 1,8-Dimercapto-3,6-dioxaoctane (DMDO) (224.36 g, 1.23 mol) was charged into the solution and the resulting mixture was stirred at 60° C. for 1 to 2 hours. Allyl glycidyl ether (280.33 g, 2.46 mol) was added. The mixture was stirred for 2 to 3 hours. After cooling to room temperature, the mixture was poured into a separation funnel. The top layer was collected and diluted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to yield 500 g of 4,11,14,21-tetraoxa-8,17-dithiatetracosa-1,23-diene-6,19-diol as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine In chloroform at 100℃; for 1h; Inert atmosphere; Microwave irradiation; | General procedure-2 (Microwave-assisted) 2,20-dithiodibenzoylchloride (2.53 mmol), pyridine (5.06 mmol), and either a dithiol ordiol (2.53 mmol) were taken in a round bottom flask, and chloroform(10 mL) was added. The reaction mixture was refluxed for 1 h under a nitrogen atmosphere in StartSYNTH-Microwave SynthesisLabstation system. (MW, E1000 W, 100 C), then left to cool toroom temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 2,2'-azobis(isobutyronitrile) In chloroform at 60℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate In tetrahydrofuran at 0 - 20℃; for 48h; | 1 Example 1 After stirring to dissolve cyanuric chloride (2 g, 10.85 mmol) in THF, potassium carbonate (3 g, 21.69 mmol) was added. ethylenedioxy diethesiol (10.59 ml, 65.07 mmol) was added at 0 ° C, and the temperature was raised to room temperature, followed by reflux reaction for 48 hours. After the reaction, the precipitate was filtered, separated by column chromatography, and then the organic solvent was dried in a vacuum oven to obtain TEOT-2. |
Yield | Reaction Conditions | Operation in experiment |
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74% | Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol In water at 20℃; for 0.5h; Stage #2: 4-Fluoro-3-nitroaniline With samarium(III) chloride hexahydrate In chloroform; water at 40℃; | Cyclothiomethylation of nitroanilines 4f,g with CH2O and 3,6-dioxa-1,8-octanedithiol (General method) General procedure: A mixture of 3,6-dioxa-1,8-octanedithiol (0.16 ml, 1 mmol) and 37% formalin (0.15 ml, 2 mmol) was stirred for 30 minat room temperature. Then a solution of nitroaniline 4f,g (1 mmol) and SmCl3·6H2O (0.02 g, 5 mol %) in 5 ml of suitable solvent (compound 4f - CHCl3, compound 4g -Me2CO) was added dropwise. The mixture was stirred for 3-4 h at 40°C, the product was then evaporated on a rotary evaporator and purified by column chromatography. 3-(4-Fluoro-3-nitrophenyl)-1,11-dioxa-4,8-dithia-6-azacyclotridecane(8a). Yield 0.27 g (74%), yellow powder,mp 114-117°C, Rf 0.76 (PhH-tOAc, 1:2). IR spectrum, ν,cm-1: 549 (C-H), 592 (C-S), 686 (C-S), 707 (C-H), 756(C-S-C), 807 (C-H), 1072 (C-O-C), 1112 (C-N), 1138(C-O-C), 1215 (C-N), 1245 (NO2-), 1266 (C-O-C),1281 (C-F), 1349 (NO2-), 1386 (O-H), 1422 (C-OH),1450 (CH2), 1539 (NO2-). 1H NMR spectrum, δ, ppm (J, Hz):2.69 (4H, t, J = 4.6, 2SCH2CH2O); 3.71 (4H, s,OCH2CH2O); 3.92 (4H, t, J = 4.6, 2SCH2CH2O); 5.11 (4H,s, SCH2NCH2S); 7.15-7.22 (2H, m, H Ar); 7.60-7.62 (1H,m, H Ar). 13C NMR spectrum, δ, ppm (J, Hz): 29.2(2SCH2CH2O); 55.0 (SCH2NCH2S); 70.2 (OCH2CH2O);74.8 (2SCH2CH2O); 109.5 (d, 4JCF = 2.2, C Ar); 118.7 (d,2JCF = 17.4, C Ar); 119.8 (d, 3JCF = 5.5, C Ar); 137.5 (d,JCF = 6.1, C Ar); 142.5 (s, C Ar); 148.5 (d, 1JCF = 203.6, C Ar). 19F NMR spectrum, δ, ppm: -132.9. Found, m/z: 361.039[M-H]+. 1418FN24S2. Calculated, m/z: 361.069. Found, %: 46.45; 5.22; N 7.81; S 17.76. 1419FN24S2.Calculated, %: C 46.39; H 5.28; N 7.73; S 17.69. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: Amixture of 3,6-dioxa-1,8-octanedithiol (0.16 ml, 1 mmol)and 37% formalin (0.15 ml, 2 mmol) was stirred for 30 minat room temperature. Then a solution of nitroaniline 4f,g (1 mmol) and SmCl3·6H2O (0.02 g, 5 mol %) in 5 ml of suitable solvent (compound 4f - CHCl3, compound 4g -Me2CO) was added dropwise. The mixture was stirred for 3-4 h at 40C, the product was then evaporated on a rotary evaporator and purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol In water at 20℃; for 0.5h; Stage #2: aniline In water at 20℃; | Cyclothiomethylation of aniline (1) (General method) General procedure: A mixture of 1,2-ethanedithiol, 1,3-propanedithiol, or 3,6-dioxa-1,8-octanedithiol (1 mmol) and 37% formalin (0.15 ml,2 mmol) was stirred for 30 min at room temperature. Aniline (1) (0.09 ml, 1 mmol) was then added dropwiseand the mixture was stirred at room temperature for 3-4 h.The product was evaporated on a rotary evaporator andpurified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With caesium carbonate In N,N-dimethyl-formamide at 50 - 60℃; for 12h; Inert atmosphere; | 2.2. Synthesis and characterization of L Cs2CO3 (6.4g, 18.1mmol) was dissolved in DMF (2 L) in a 3 L round-bottom flask. 3,6-Dioxa-1,8-octane-dithiol (2.3g, 12.8mmol) and dichloride 6 (5.1g, 13.1mmol) were dissolved in DMF (1.0L) and placed in a dropping funnel. The contents of the dropping funnel were added dropwise into the DMF solution under a nitrogen atmosphere at 50-60°C for 12h. After being cooled to room temperature, the reaction mixture was filtered and the solvent evaporated. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered and the solvent was removed to give a yellow crude mixture. Flash column chromatography (SiO2, n-hexane/ethyl acetate=7:3) afforded the product as a white solid in 20% yield. Mp: 120-121°C. IR (KBr, pellet) 2923, 2859, 2362, 2343, 1654, 1597, 1493, 1449, 1246, 1105, 1091, 1047, 1020, 781, 749cm-1. Anal. Calcd for [C27H31NO4S2]: C, 65.16; H, 6.28; N, 2.81; S, 12.88. Found: C, 65.22; H, 6.24; N, 2.85; S, 13.27. 1H NMR (see Fig. S1a, 300MHz, CDCl3, δ): 7.88-6.96 (11H, aromatic), 5.22 (s, 4H, PyCH2O), 3.87 (s, 4H, OCH2CH2O), 3.37 (t, 4H, OCH2CH2S), 3.22 (s, 4H, ArCH2S), 2.56 (t, 4H, SCH2CH2O); 13C NMR (see Fig. S1b, 75MHz, CDCl3, δ) 156.6, 155.9, 139.9, 131.7, 129.8, 125.4, 125.1, 121.7, 113.0, 70.3 69.6, 69.0, 33.7, 33.6. MS (ESI) m/z: 520.25 [L·Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 20℃; for 15h; | 2.1 Example 2.1 : Synthesis of compound 1 1 Synthesis of the monoacetylated dithiol was firstly carried out. To this end, 3 mmol of the corresponding dithiol (547 mg of 2,2'-(ethylenedioxy)diethanethiol for the synthesis of molecule 1 1 ) was dissolved in 17 mL of DCM in a round bottom flask. Thereafter, 17 mL of pyridine and 282 μΙ of acetic anhydride (1 .5 mmol) were added stirring at room temperature for at least 15 hours. After this time, the solvent was removed in vacuo and extraction was effected with several washes adding water in order to remove the pyridine. There was thus obtained a product mixture comprising 71 % the desired monoacetylated product, 27% the diacetylated product (without free thiol), and in <2% the dithiol of the starting material. This mixture was used without further purification to carry out the Michael reaction, considering the percentage of purity of the monoacetylated product, and taking into account that of the formed by-products, the diacetylated compound is inert to the nucleophilic addition, and the dithiolated compound is found in residual proportion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,6-dioxa-1,8-octandithiol; acetic anhydride With pyridine In dichloromethane at 20℃; for 15h; Stage #2: ortoquinone With trifluoroacetic acid In dichloromethane for 6h; Inert atmosphere; | 2.1 Example 2.1 : Synthesis of compound 1 1 Synthesis of the monoacetylated dithiol was firstly carried out. To this end, 3 mmol of the corresponding dithiol (547 mg of 2,2'-(ethylenedioxy)diethanethiol for the synthesis of molecule 1 1 ) was dissolved in 17 mL of DCM in a round bottom flask. Thereafter, 17 mL of pyridine and 282 μΙ of acetic anhydride (1 .5 mmol) were added stirring at room temperature for at least 15 hours. After this time, the solvent was removed in vacuo and extraction was effected with several washes adding water in order to remove the pyridine. There was thus obtained a product mixture comprising 71 % the desired monoacetylated product, 27% the diacetylated product (without free thiol), and in <2% the dithiol of the starting material. This mixture was used without further purification to carry out the Michael reaction, considering the percentage of purity of the monoacetylated product, and taking into account that of the formed by-products, the diacetylated compound is inert to the nucleophilic addition, and the dithiolated compound is found in residual proportion. For Michael addition, in a 250 mL volume bottom flask, a solution of 234 mg of Nal04 (1 mmol) in 38 mL of H2O was prepared and cooled in an ice bath. 1 10 mg of pyrocatechol (1 mmol) dissolved in 1 mL of Et.20 was then added and left stirring vigorously for 15 min. After this time, extraction of the formed o-quinone with the addition of dichloromethane (DCM, 4x8mL) was carried out. Thereafter, it was dried over anhydrous sodium sulfate and filtered. On the other hand, a solution of 315 mg of monoacetylated dithiol previously prepared (approx. 1 mmol, considering a purity of =71 %) in 2 mL of dichloromethane was prepared in an inert atmosphere in a Schlenk flask. To this solution 229.5 μΙ of trifluoroacetic acid (TFA, 3 mmol) was further added. Finally, the solution of the o-quinone in DCM was added to the solution containing the thiol, further protecting the mixture from light and leaving it under magnetic stirring under an inert atmosphere for six hours. After this time, both the solvent and the TFA were removed under vacuum to obtain the reaction crude. The product mixture was purified using a chromatography column with a 7/3 hexane/ethyl acetate eluent mixture in a yield of 38% of product 1 1. Characterization of 11 :1H-NMR (360 MHz, CDCI3) δ 7.60 (broad, 1 H), 6.99 (dd, Ji = 1 .5 Hz, J2= 7.8 Hz, 1 H), 6.91 (dd, Ji = 1 .5 Hz, J2= 8.2 Hz, 1 H), 6.73 (t, J= 7.9 Hz, 1 H), 5.89 (broad, 1 H), 3.65 (broad, 4H), 3.61 (t, J = 6.6 Hz, 2H), 3.55 (t, J = 5.7 Hz, 2H), 3.1 1 (t, J = 6.7 Hz, 2H), 2.91 (t, J = 5.7 Hz, 2H), 2.33 (s, 3H); 13C-NMR (360 MHz, CDCI3) δ 196.14, 145.79, 144.90, 127.57, 120.75, 1 18.77, 1 16.75, 70.36, 70.24, 70.06, 68.99, 36.88, 30.86, 28.99; (0399) MS/ESI- [M-H]" 332.075 Da. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid In dichloromethane for 6h; Inert atmosphere; | 5 Example 5: Synthesis of compound 16: In a 250 mL volume bottom flask, a solution of 234 mg of Nal04 (1 mmol) in 38 mL of H2O was prepared and cooled in an ice bath. 1 10 mg of pyrocatechol (1 mmol) dissolved in 1 mL of Et.20 was then added and left stirring vigorously for 15 min. After this time, extraction of the formed o-quinone with the addition of dichloromethane (DCM, 4x8mL) was carried out. Thereafter, it was dried over anhydrous sodium sulfate and filtered. On the other hand, a solution of 73 mg of 2,2'-(ethylenedioxy) diethanethiol (0.5 mmol) in 2 mL of dichloromethane was prepared in an inert atmosphere in a Schlenk flask. To this solution 229.5 μΙ of trifluoroacetic acid (TFA, 3 mmol) was further added. Finally, the solution of the o-quinone in DCM was added to the solution containing the dithiol, further protecting the mixture from light and leaving it under magnetic stirring under an inert atmosphere for six hours. After this time, both the solvent and the TFA were removed in vacuo to obtain crude with products 16 and 12. The product mixture was purified using a chromatography column with a 7/3 hexane/ethyl acetate elution mixture with a total yield of 51 % (37.3% of the bipodal derivative 16 and 20.7% of the monopodal product 12). Characterization of 16: 1H-NMR (400 MHz, CDCI3) δ 7.65 (broad, 1 H), 7.01 (dd, Ji = 1.5 Hz, J2= 7.8 Hz, 2H), 6.93 (dd, Ji = 1.5 Hz, J2= 8.0 Hz, 2H), 6.76 (t, J= 7.8 Hz, 2H), 5.85 (broad, 1 H), 3.70 (s, 4H), 3.57 (t, J = 5.8 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H).13C-NMR (400 MHz, CDCIs) δ 145.77, 144.84, 127.75, 121 .04, 1 18.65, 1 17.01 , 70.23, 68.98, 36.96; MS/ESI- [M- H]" 398.086 Da. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: formaldehyd; 3,6-dioxa-1,8-octandithiol With samarium(III) chloride hexahydrate In chloroform at 20℃; for 0.5h; Stage #2: N-butylamine In chloroform at 0 - 20℃; for 3h; | General procedure for cyclothiomethylation of aliphatic amines with formaldehyde and α,ω-dithiols. General procedure: A mixture of 1 mmol of aliphatic α,ω-dithiol (or 0.16 mL of 3,6-dioxa-1,8-octanedithiol) and formalin (37%, 2 mmol, 0.15 mL) in 1 mL of chloroform was stirred at room temperature (~20°) for 30 min, then cooled to 0°C. After adding of 1 mmol of primary amine, the mixture was stirred for 3 h at 20°C in chloroform, then extracted with chloroform. The organic phase was dried with MgSO 4 . After removal of the solvent, the residue was chromato-graphed. Synthesis of compounds 4b-4e was carried out similarly using 5 mol% of SmCl 3 ·6H 2 O as a catalyst. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol at 65℃; for 3h; Overall yield = 42 %; Overall yield = 150 mg; | Preparation of Macrocycles 7a-g and 8a-b; General Procedure General procedure: To a solution of corresponding dithiol 1d-f (1 mmol) in MeOH (50 mL) and appropriate carbonate (sodium, potassium or cesium) (1 mmol, 0.5 g) a solution of bis-epoxide of type 3 (1 mmol) in MeOH (5 mL) was added. The mixture was stirred at 65 °C for 3 h. The solution was extracted with methylene chloride (3 × 20 mL) and the combined organic layer were dried over anhydrous magnesium sulfate and then solvent was evaporated. The final product was isolated by flash chromatography (chloroform: 5% methanol) on silica gel and additionally by preparative thin-layer chromatography using chloroform as solvent. The macrocycles 7a-g and 8a-b were obtained as pale-yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In methanol at 65℃; for 3h; | Preparation of Macrocycles 7a-g and 8a-b; General Procedure General procedure: To a solution of corresponding dithiol 1d-f (1 mmol) in MeOH (50 mL) and appropriate carbonate (sodium, potassium or cesium) (1 mmol, 0.5 g) a solution of bis-epoxide of type 3 (1 mmol) in MeOH (5 mL) was added. The mixture was stirred at 65 °C for 3 h. The solution was extracted with methylene chloride (3 × 20 mL) and the combined organic layer were dried over anhydrous magnesium sulfate and then solvent was evaporated. The final product was isolated by flash chromatography (chloroform: 5% methanol) on silica gel and additionally by preparative thin-layer chromatography using chloroform as solvent. The macrocycles 7a-g and 8a-b were obtained as pale-yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: bis-(dimethylamino)methane; 3,6-dioxa-1,8-octandithiol With samarium(III) chloride hexahydrate In chloroform at 20℃; for 0.5h; Stage #2: Cyclopropylamine In ethanol; chloroform at 20℃; for 3h; | General procedure for heterocyclization of carbocyclicamines. General procedure: A mixture of N,N,N1,N1-tetramethylmethanediamine(0.27 mL, 2 mmol), 3,6-dioxa-1,8-octanedithiol (0.16 mL, 1 mmol) in 5 mL of CHCl3 and SmCl3.6H2O (0.018 g, 0.05 mmol) was stirred at room temperature for 30 min, then the corresponding cycloalkylamine (1 mmol) in 5 mL of EtOH was added dropwise.The reaction mixture was stirred for 3 h at ~20°C and then evaporated. The residue was chromatographed on a SiO2column obtaining pure heterocycles 4-8.6-Cyclopropyl-1,11-dioxa-4,8-dithia-6-azacyclotridecane(4). Yield 0.20 g (76%), colorless oil, Rf 0.7(toluene-ethyl acetate-acetone, 4:1:1). Spectral characteristicsare identical to those described in |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: bis-(dimethylamino)methane; 3,6-dioxa-1,8-octandithiol With samarium(III) chloride hexahydrate In chloroform at 20℃; for 0.5h; Stage #2: Cyclopentamine In ethanol; chloroform at 20℃; for 3h; | General procedure for heterocyclization of carbocyclicamines. General procedure: A mixture of N,N,N1,N1-tetramethylmethanediamine(0.27 mL, 2 mmol), 3,6-dioxa-1,8-octanedithiol (0.16 mL, 1 mmol) in 5 mL of CHCl3 and SmCl3.6H2O (0.018 g, 0.05 mmol) was stirred at room temperature for 30 min, then the corresponding cycloalkylamine (1 mmol) in 5 mL of EtOH was added dropwise.The reaction mixture was stirred for 3 h at ~20°C and then evaporated. The residue was chromatographed on a SiO2column obtaining pure heterocycles 4-8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: bis-(dimethylamino)methane; 3,6-dioxa-1,8-octandithiol With samarium(III) chloride hexahydrate In chloroform at 20℃; for 0.5h; Stage #2: cyclohexylamine In ethanol; chloroform at 20℃; for 3h; | General procedure for heterocyclization of carbocyclicamines. General procedure: A mixture of N,N,N1,N1-tetramethylmethanediamine(0.27 mL, 2 mmol), 3,6-dioxa-1,8-octanedithiol (0.16 mL, 1 mmol) in 5 mL of CHCl3 and SmCl3.6H2O (0.018 g, 0.05 mmol) was stirred at room temperature for 30 min, then the corresponding cycloalkylamine (1 mmol) in 5 mL of EtOH was added dropwise.The reaction mixture was stirred for 3 h at ~20°C and then evaporated. The residue was chromatographed on a SiO2column obtaining pure heterocycles 4-8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: bis-(dimethylamino)methane; 3,6-dioxa-1,8-octandithiol With samarium(III) chloride hexahydrate In chloroform at 20℃; for 0.5h; Stage #2: cycloheptanamine In ethanol; chloroform at 20℃; for 3h; | General procedure for heterocyclization of carbocyclicamines. General procedure: A mixture of N,N,N1,N1-tetramethylmethanediamine(0.27 mL, 2 mmol), 3,6-dioxa-1,8-octanedithiol (0.16 mL, 1 mmol) in 5 mL of CHCl3 and SmCl3.6H2O (0.018 g, 0.05 mmol) was stirred at room temperature for 30 min, then the corresponding cycloalkylamine (1 mmol) in 5 mL of EtOH was added dropwise.The reaction mixture was stirred for 3 h at ~20°C and then evaporated. The residue was chromatographed on a SiO2column obtaining pure heterocycles 4-8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: bis-(dimethylamino)methane; 3,6-dioxa-1,8-octandithiol With samarium(III) chloride hexahydrate In chloroform at 20℃; for 0.5h; Stage #2: cyclooctylamine In ethanol; chloroform at 20℃; for 3h; | General procedure for heterocyclization of carbocyclicamines. General procedure: A mixture of N,N,N1,N1-tetramethylmethanediamine(0.27 mL, 2 mmol), 3,6-dioxa-1,8-octanedithiol (0.16 mL, 1 mmol) in 5 mL of CHCl3 and SmCl3.6H2O (0.018 g, 0.05 mmol) was stirred at room temperature for 30 min, then the corresponding cycloalkylamine (1 mmol) in 5 mL of EtOH was added dropwise.The reaction mixture was stirred for 3 h at ~20°C and then evaporated. The residue was chromatographed on a SiO2column obtaining pure heterocycles 4-8. |