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 (2x20mL). 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 (2x100mL). 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 (2x100mL). The aqueous extracts were washed with ether (100mL), combined and acidified with 4M HCl (gas evolution) . Extraction with chloroform (150 mL, then 2x50mL) 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.

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)

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 (2x100mL). 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)

Out on vacation

I am taking a week off. The next update will appear probably on Monday 23rd. Thank you for reading Org Prep Daily. Please, let me know if you want to have your synthetic procedures posted here. (‘Call For Authors’, Oct 8).

  Credit: Adolf Born

Bis-(4-morpholino)-methane

37% aq. formaldehyde 81.2g (1.00 mol, Fisher, methanol-stabilized grade) was cooled on ice bath and morpholine 175.0mL (2.00 mol) was added in 20 mL portions over 20 min with vigorous stirring on ice bath (exothermic!).The reaction was continued at 0-5C for additional 1 hour and then at RT for 2 hours. The reaction mixture was concentrated on rotavap (50 to 5 Torr, RT to 50C) and the remaining liquid was distilled at reduced pressure, b.p. 102-105C/5 Torr. Y=167.44g (90%) of a slightly oily colorless liquid. 1H(CDCl3, 400MHz): 3.690(app t, 4.7Hz, 8H), 2.902(s, 2H), 2.495(app br t, 4.5Hz, 8H); 13C(CDCl3, 100MHz): 81.94, 67.33(4C), 52.35(4C)

Using the above procedure on half the scale, bis(1-pyrrolidino)-methane was obtained from 37% HCHO 40.6g (500mmol) and pyrrolidine 83.5mL (1.00mol) in 77% yield (59.33g) as a colorless liquid, bp 65-67C/6Torr. 1H(CDCl3, 400MHz): 3.213(s, 2H), 2.581(m, 8H), 1.772(m, 8H); 13C(CDCl3, 100MHz): 77.76, 52.98(4C), 23.75(4C)

These preparations are modified (simplified workup) from a procedure published in Tetrahedron 53/8 2941-58 (1997)

Bis-morpholinomethane and bis-pyrrolidinomethane are useful reagents for aminomethylating electron-rich heterocycles (pyrroles, indoles) and active-methylene compounds in presence of TFA. Even more electrophilic reagent, [CH2=NR2+]Cl- can be generated from these bis-aminomethanes in quantitative yield with 1 eq. of acetyl chloride (anh. Et2O, 0C to RT, the iminium salt precipitates in a nearly quantitative yield. Very hygroscopic.).

Spirochromanones

Pyrrolidine 0.25mL (3.0mmol) was added to a mixture of 2-hydroxy-5-chloroacetophenone 6.176g (36.2mmol) and 1-acetyl-4-piperidone 5.113g (36.2mmol)  in methanol 12mL. The mixture was heated under reflux (Ar, oil bath 80C) for 11 hours. The reaction mixture was diluted with ether 80mL and allowed to crystallize at RT for 1 hour. The precipitated product was collected by filtration, washed with ether (2x20mL) and dried on highvac. Y=8.286g (78%) of a white crystalline solid.

1H(d6-DMSO, 400MHz): 7.658(m, 2H), 7.151(d, 8.7Hz, 1H), 4.084(app br d, 10.0Hz, 1H), 3.632(app br d, 13.9Hz, 1H), 3.360(m, 1H), 2.966(td, t:12.5Hz, d:3.0Hz, 1H), 2.876(s, 2H), 2.003(s, 3H), 1.900(app br t, 16.0Hz, 2H), 1.721(m, 1H), 1.569(m, 1H)

 

The same procedure and scale, Y=8.487g (76%) of a white crystalline solid 1H(d6-DMSO, 400MHz): 7.641(s, 1H), 7.149 (s, 1H), 4.089(app br d, 13.3Hz, 1H), 3.630(app br d, 13.9Hz, 1H), 3.347(m, 1H), 2.948(td, t:12.5Hz, d:2.8Hz, 1H), 2.833(s, 2H), 2.341(s, 3H), 2.002(s, 3H), 1.894(app br t, 16.0Hz, 2H), 1.716(m, 1H), 1.564(m, 1H)  

  

Pyrrolidine 0.455mL with 2-hydroxy-5-fluoroacetophenone 10.110g (65.59mmol) and 1-acetyl-4-piperidone 5.113g (65.59mmol)  in methanol 22mL was heated under reflux (Ar, oil bath 80C) for 10 hours. The reaction mixture was diluted with ether 150mL and allowed to crystallize at RT for 8 hours. The precipitated pure product (11.176g) was collected by filtration, washed with ether (4x20mL) and dried on highvac. Cooling the supernatants to 5C (fridge, over weekend), additional product 3.930g precipitated. This second crop was re-crystallized from a mixture benzene-cyclohexane 1:2 to provide 3.761g of a pure product. Combined Y=14.937g (82%) of a light tan crystalline solid

1H(d6-DMSO, 400Mz): 7.494(td,t:8.4Hz,d:3.2Hz,1H), 7.436(dd,8.4Hz,3.2Hz, 1H), 7.160(dd,9.0Hz.4.3Hz,1H), 4.090(br m, 1H), 3.638(br m, 1H), 3.370(m, 1H), 2.976(m, 1H)2.870(s, 2H), 2.009(s, 3H), 1.906(app br t, 2H), 1.726(m, 1H), 1.575(m, 1H); 19F(d6-DMSO, 376.5MHz): -121.92 (m, 1F)