credit: A. Lee Bennett
I am taking another week off. The next update will probably appear here on November 6. Thank you for reading Org Prep Daily.
October 27, 2006
A tricyclic monster and 3-(p-hydroxybenzyl)-5-(o-aminophenyl)-1,2,4-triazole
2-isothiocyanato-benzonitrile 1.603g (10.0mmol, Transworld) was added to a slurry of p-hydroxyphenacetyl hydrazide 1.662g (10.0mmol) in anhydrous ethanol 100mL and the mixture was stirred for 30 min, then refluxed vigorously under Ar for 4 hours (oil bath 120-140C). The reaction mixture was let to crystallize at RT for 16hours (overnight). The precipitated product was collected by filtration, washed with anh EtOH and dried on highvac. Y=2.870g (93%) of a white crystalline solid. 1H(d6-DMSO, 400MHz): 13.909(br s, 1H), 9.259(s, 1H), 8.161(dd, 7.8Hz, 0.8Hz, 1H), 7.757(td, t:8.6Hz,d:1.6Hz, 1H), 7.638(d, 7.8Hz, 1H), 7.484(app t, 7.0Hz, 1H), 7.151(app d, 8.6Hz, 2H), 6.702(app d, 8.6Hz, 2H), 4.113(s, 2H); LC/MS: +ESI 309 (M+1)
The thiocarbonyl tricyclic compound from the previous step, 1.542g (5.00mmol) was suspended in water 150mL and 15% NaOH solution 1.5mL was added. The mixture was stirred and sonicated for 15 min (until a clear solution formed). Neat methyl iodide 0.50mL (1.10g) was added dropwise and the mixture was stirred at RT for 2 hours. 1M NaHCO3 solution 100mL was then added, the mixture was stirred for 15 min, the precipitate was collected by filtration, washed with water and dried on highvac. Y=1.610g (100%) of the methylthio compound as a white cryst solid (about 95% pure, containing a trace of the thiocarbonyl starting material). 1H(d6-DMSO, 600MHz): 9.277(s, 1H), 8.320(app d, 1H), 7.922(app d, 1H), 7.855(app t, 1H), 7.667(dd, 7.9Hz,0.9Hz, 1H), 7.159(app d, 8.2Hz, 2H), 6.702(app d, 8.2Hz, 2H), 4.160(s, 2H), 2.762(s, 3H)
The methylthio compound from the previous step 471mg (1.461mmol) and 15% aq. NaOH 60mL was refluxed on oil bath (190C) for 8 hours. The cooled reaction mixture was acidified by adding concentrated HCl 26mL and the mixture was cooled on ice bath. The small amount of insoluble material (probably silica from dissolved glass) was removed by filtration and the filtrates were made basic with saturated bicarbonate (gas evolution). The precipitated crude product (containing some inorganics) was collected by filtration. The solids were suspended in a mixture ethyl acetate-methanol 2:1 (about 100mL), heated to reflux, cooled,filtered and the filtrates were evaporated. The residue was dried on highvac. Y=394mg (100%) of a white crystalline solid.
1H(d6-DMSO, 400MHz): 7.786(dd, 7.8Hz, 1.2Hz, 1H), 7.068(m, 3H), 6.724(dd, 7.4Hz, 8.2Hz, 1H), 6.679(app d, 8.2Hz, 2H), 6.547(app t, 7.6Hz, 1H), 6.498(br s, 2H), 3.958(s, 2H); LC/MS(+ESI): 267 (M+1)
In this case, the S-methylation was unnecessary for the final hydrolysis but we needed the methylthio derivate for other work (i.e. exchange with amines). A procedure for preparation of p-hydroxyphenacetyl hydrazide was posted on Oct 10.
o-isocyanatobenzonitrile reacts analogously to the isothiocyanato-benzonitrile. Other solvents than EtOH could be used (DMF works well) but the cyclization of the thiosemicarbazide intermediate is faster in protic solvents.
October 25, 2006
2-(2′,6′-dichlorophenyl)-2-fluoroacetic acid
2,6-dichlorobenzaldehyde 7.000g (40.0mmol) and anhydrous ZnI2 65mg was dissolved in anh dichloromethane 10mL with gentle heating on heat gun under Ar. The solution was placed on ambient water bath and TMSCN 5.60mL (42mmol) was added dropwise over 10 min period. The mixture was stirred at RT for 90 min, then cooled on ice bath. Neat DAST 6.00mL (45 mmol, Aldrich) was carefully added dropwise over 10 min (exothermic!). The mixture was stirred at 0C for 1 hour and then at RT for 2 hours. The reaction mixture was diluted with a common-grade dichloromethane (100mL), cooled to 0C and carefully quenched by addition of ice-cold water 50mL followed by 2M HCl 50mL. The mixture was stirred at RT for 15 min, separated, the aqueous phases were re-extracted with dichloromethane (2×20mL). The extracts were washed with sat. NaHCO3 (100mL), combined, dried (MgSO4) and evaporated. The residue was purified on a column of silica in a mixture hexane-ethyl acetate 40:3. The purified oily product was placed into a freezer overnight and the obtained crystalline mass was then dried on highvac. Y=6.136g (75%) of the fluoronitrile as a sticky, low-melting light tan solid. 1H(CDCl3, 400MHz): 7.428(m, 3H), 6.826(d, 44Hz, 1H); 19F(CDCl3, 376.6MHz): -179.58 (d, 45Hz, 1F)
The fluoronitrile intermediate 6.130g (30.04mmol) was combined with 50% H2SO4 (540g) in a 1L round flask and the heterogennous mixture was stirred on oil bath at 80-90C for 18 hours. The resulting heterogennous mixture was cooled to RT, diluted with water 0.5L and chloroform 300mL, separated, the aqueous phase was re-extracted twice with chloroform (2×100mL). The org extracts were washed with brine 400mL, combined, dried (MgSO4) and evaporated. The obtained yellow semi-solid residue was suspended in ether 100mL, a solution of potassium carbonate 5.0g in water 200mL was added and the mixture was stirred for 30 min. The aqueous phase was separated, the org phase was re-extracted twice with water (2×100mL). The aqueous extracts were washed with ether (100mL), combined and acidified with 4M HCl (gas evolution) . Extraction with chloroform (150 mL, then 2×50mL) followed by washing the org. extracts with brine, drying with MgSO4 and evaporating the extracts provided a pure product that solidified on highvac. Y=3.094g (46%) of a white crystalline solid.
1H(CDCl3, 400MHz): 8.357(very br s, 1H), 7.377(m, 2H), 7.337(m, 1H), 6.582(d, 45Hz, 1H); 19F(CDCl3, 376.5MHz): -183.66(d, 45Hz, 1F)
TMS-CN is very poisonous (generates HCN instantly with moisture). DAST is extremely corrosive, it reacts with water with huge exotherm and also generates HF. Always use good gloves (if using thin disposable gloves, double them), work in the hood, do not spill and add it slowly, to avoid “bumping”. Having a face shield (or a hood sash down) is a good idea, especialy with larger scales. HF burns are exceptionaly nasty and painful, Ca-gluconate ointment is used as antidote.
TMS-cyanohydrine formation followed by OTMS exchange for F with DAST or Deoxyfluor reagent is a convenient alternative to enolate electrophilic fluorination. The next step - alpha fluoronitrile hydrolysis - has to be done rather carefully: using a more concentrated sulfuric acid or increasing the reaction temperature produces the o,o-dichloromandelic acid due to alpha F hydrolysis.
October 24, 2006
1-Boc-2-(5′-indolyl)-4,5-dihydroimidazole
P2S5 0.55g was added to a mixture of 5-cyanoindole 10.00g (70.34mmol) in neat ethylene diamine 90mL in a pressure glass flask (H2S gas evolution), the flask was closed, mixture sonicated for 10 min and the obtained homogennous mixture was stirred at 120C for 14 hours (overnight). The amine was evaporated on highvac (30 to 0.5Torr, RT to 30C), the residue was suspended in a mixture of dichloromethane 150mL and water 50mL, the mixture was heated to reflux, stirred for 10 min, cooled, diluted with hexane 200mL, stirred for 15 min. The solids were collected by filtration, washed with hexane 200mL and then with ice-cold water (50mL), dried by suction and on highvac. Y=12.011g (92%) of a off-white solid. 1H(d6-DMSO, 400MHz): 11.274(br s, 1H), 8.009(br d, 1.2Hz, 1H), 7.645(dd, 8.6Hz, 1.6Hz, 1H), 7.389(m, 1H), 7.368(m, 1H), 6.741(br s, 1H), 6.479(br d, 3.1Hz, 1H), 3.589(s, 4H)
The indolylimidazoline from the previous step 11.910g (64.30mmol) was suspended in acetone 100mL, solid Boc anhydride 15.28g (70 mmol) was added followed by additional acetone 20mL (to wash the funnel). With vigorous stirring, water 150mL was slowly added over 10 min period, followed by 15% aq. NaOH 15mL. The stirring was continued overnight (13 hours), the formed precipitate was collected by filtration, washed thoroughly with a mixture water+acetone 3:1 (100mL), dried by suction and on highvac. Y=15.208g (83%) of a white crystalline solid
1H(d6-DMSO, 400MHz): 11.194(br s, 1H), 7.660(m, 1H), 7.368(m, 2H), 7.206(dd, 8.6Hz, 2.0Hz, 1H), 6.467(m, 1H), 3.885(m, 2H), 3.795(m, 2H), 1.149(s, 9H)
P2S5 catalyst is not essential for the nitrile reaction, for example 5-cyanooxindole 0.886g (5.602mmol) with 5.5mL of ethylenediamine at 105C in 5 h provided 0.851g (75.5%) of the corresponding imidazoline-oxindole. (After purification on silica 35g in chloroform/MeOH+aq. NH3 10:1 mixture, using a gradient from 10 to 35% of the MeOH+NH3 mix)
October 23, 2006
Noyori asymmetric transfer hydrogenation
RuCl2(cymene) 24mg (Aldrich, 0.04mmol Ru) and (S,S)-TsDPEN 40mg (0.096mmol, Aldrich) in a 250mL (14/20 joint) round flask equipped with a stopcock was flushed with Ar using a long needle. Dichloromethane (4mL, from Aldrich SureSeal) was added and the mixture was stirred under Ar (without reflux condenser) on 40C oil bath for 1 hour. The Ru-salt and the ligand dissolved. After 1 h, the solvent was removed by blowing a stream of Ar into the flask on the 40C bath. De-ionised water 16mL was added into the dry flask (with a film of active catalyst on the wall) and was de-gassed by vac/Ar purge (3-times). A mixture of solid HCO2Na 2.72g (40mmol), CTAB 15mg (0.04mmol) and the starting F-spiroketone 1.110g (4.0 mmol) was added and the flask was flushed with a stream of Ar. Ethyl acetate 2 mL (a good grade, not deoxygenated) was added and the mixture was stirred vigorously under Ar at 40C for 16 hours (the crystals of the starting material gradualy dissolved, the progres was monitored by TLC). The cooled reaction mixture was extracted twice with EtOAc (2×100mL). The combined extracts were dried (with 4A powdered molecular sieves), filtered and evaporated. The residue was purified on a column of silica (80g) in a gradient of methanol in chloroform, 0 to 2.7% of MeOH, then 2.7% isocratic. Y=1.123g (100%) of a light-yellow sticky glass.
The optical purity was assayed using a reverse-phase chiral HPLC column, Chiralpak AD-RH, in water-acetonitrile (no TFA) at 50 or 55C, at 0.8mL/min. The e.r. was 0.5:99.5 by integration. The opposite ligand enantiomer provided 100%Y of the product with e.r. = 99.4:0.6 (with the minor enantiomer peak eluting on the tail of the main one).
The 1H-NMR spectra in DMSO show a 1:1 mixture of rotamers about the amide bond. 1H(d6-DMSO, 400MHz): 7.168(dd, 9.4Hz, 3.1Hz, 1H), 6.977(td, t:8.6Hz, d:3.1Hz, 1H), 6.802(dd, 9.0HZ, 4.8Hz, 1H), 5.509(dd, 6.0Hz, 2.7Hz, 1H), 4.672(m, 1H), 4.039(m, 1H), 3.595(m, 1H), 3.411(m, 0.5H), 3.282(m, 0.5H), 3.049(m, 0.5H), 2.919(m, 0.5H), 2.086(m, 1H), 2.008(s, 1.5H), 1.993(s, 1.5H), 1.805-1.469(m, 5H)
