PMGB

Here are some tips from my experience.

Filtration: Kimberly-Clark Professional Single-Fold paper Towels can be used as the filter paper (probably cheapest) to filter out sodium sulfate. Filtration is generally faster than normal filter paper.

Column Chromatography: Rubber bulb set for pumping air (available from VWR, Catalog No. 56335-003) in flash column chromatography is much safer to operate. Accidents due to high air pressure in the column when using in-house nitrogen gas can easily be avoided by using this technique. Properly cut round filter paper can be used in place of sand to cover the silica gel or alumina in the column. 

Reflux Condenser cooling: In-house air can be used in the condenser at night for avoiding water flooding problem. Alternatively house vacuum (in the outlet of the condenser) can be used to pass the air through the condenser (keeping the inlet open for sucking atmospheric air).

Thiol smell: Commercial bleach is used to prewash the glassware used in the reaction invoving ethanethiol inside the hood to prevent the smell going out.  

Nitrogen Balloon: Insert one balloon (12” round helium quality) in another (double balloon).  Insert the double balloon in one inch tubing (5/16’’ ID, VWR Cat. No. 60985-536) and then insert to a T-joint (so you don’t need to tie the balloon to the T joint) and then fill the balloon with nitrogen. The erectile dysfunction of the balloon can be solved by putting its neck inside a cut-out 24 mL syringe.

Case 1: Amidation using DCC and DMAP: 

A mixture of aromatic carboxylic acid (0.025 mol), amine (0.025 mol), dicyclohexylcarbodiimide (DCC) (0.025 mmol), 4-(dimethylamino) pyridine (DMAP) (0.025 mmol) in 200 mL dichloromethane was stirred at room temperature for 1 h. The clear solution became turbid after 5 minutes. The solid (dicyclohexyl urea) precipitated was filtered and washed with dichloromethane; the combined filtrate and washings was washed with saturated aqueous citric acid solution (to remove amine and DMAP) and water, dried (MgSO₄) and evaporated to give the corresponding amide which was purified by triturating with ethyl acetate (white solid, 76%).

Case 2: Amidation using NHS/DCC:

To a solution of the aliphatic carboxylic acid (0.012 mol) and N-hydroxysuccinimide (NHS) (0.013 mol) in 20 mL THF was added dicyclohexylcarbodiimide (DCC) (0.013 mol) and stirred at room temperature for overnight (12 h). The clear solution became turbid after 10 minutes. The reaction mixture was filtered to remove the white precipitate (dicyclohexylurea), washed the precipitate with 50 mL THF. To the combined filtrate and washings was added the amine HCl salt (0.01 mol) followed by sodium bicarbonate (0.07 mol). Then 20 mL of water was added and the heterogeneous mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was concentrated, the residue was diluted with dichloromethane, washed with water and dried (MgSO₄) to give the corresponding amide which was purified by silica gel column chromatography using a gradient of hexanes and ethyl acetate (oil, 85%).

Case 3: Carboxamide

A mixture of the aromatic ethyl ester (0.05 mol) and ammonia (7N solution in methanol, 0.25 mol) in a sealed tube was heated to 50 ^oC for overnight (12 h). The solvent was evaporated to give the corresponding carboxamide which was purified by triturating with ether (orange solid, 84%).

Case 4: from acid chlorides

To a stirred suspension of the aliphatic amine hydrochloride salt (0.02 mol) in 25 mL DCM cooled by ice bath was added aliphatic acid chloride (0.02 mol) followed by triethylamine (0.03 mol) drop wise. The resulting mixture was stirred at room temperature for overnight (12 h). The reaction mixture was diluted with 50 mL water, extracted with 50 mL dichloromethane, washed with saturated NaHCO₃ solution, dried (MgSO₄) and evaporated to give the corresponding amide which was purified by silica gel column chromatography using a  gradient of hexane and ethyl acetate (colorless oil, 22%).

pyrimidinone:

A mixture of carboxamide (0.007 mol) and potassium tert-butoxide (0.011 mol) in 20 mL tert-butanol (caution- highly flammable reagent) was heated in a sealed tube at 90 ^oC for 6 h. The reaction mixture was cooled, tert-butanol was removed in rotavap and the residue was added to ice. Stirring for a while gave a solid (product) which was filtered, washed with water and then ether, and dried to give the corresponding pyrimidinone (white solid, 96% yield).

Reference: Dale, D J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Proc. Res. Dev. 2000, 4, 17-22.

Pyrazole esters:

To a mixture of diethyloxalate (0.07 mol) and the ketone (0.07 mol) cooled in a water bath was added sodium methoxide in portions (0.07 mol) (exothermic). The mixture was heated to 55 ^oC for 1 h. Then it was acidified with 50 mL saturated aqueous citric acid solution and extracted with 50 mL dichloromethane, dried (MgSO₄) and evaporated to give a yellow oil. To the yellow oil (intermediate) in 50 mL ethyl acetate in a water bath was added p-toluenesulfonic acid (0.3 g) followed by hydrazine hydrate (6 mL) in 25 mL ethyl acetate drop wise (exothermic) and stirred at room temperature for 1 h (yellow solid precipitated). The mixture was neutralized with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with brine and dried (Na₂SO₄) to give the corresponding mixture of pyrazoles (brown oil, 95%).    

Reference: European Patent 1 077 214 A1

To a solution of the primary amine (0.002 mol) in anhydrous ethanol was added paraformaldehyde (0.002 mol). The resulting mixture was stirred at reflux for 1 h. The paraformaldehyde completely dissolved. Sodium borohydride (0.002 mol) was added and refluxed for 1 h. The solvent was removed; the residue was diluted with dichloromethane, washed with saturated aq. NaHCO₃ solution, dried (Na₂SO₄) and evaporated to give the corresponding mono N-methyl product which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate (colorless oil, 74%).

References:
1.http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/amphetamine.methylation.html
2. http://www.alsnotebook.com/reductalk.html

3. Bhattacharyya, S. Synth. Commun. 1995, 25, 2061-2069.

Case 1: using potassium carbonate

A mixture of the phenol (0.001 mol), potassium carbonate (0.002 mol) and aliphatic bromide (0.001 mol) was heated at 65 ^oC for 2 h. The reaction mixture was cooled to room temperature; filtered, washed the precipitate with 10 mL acetone and the combined filtrate and washings was evaporated. The residue was diluted with 50 mL dichloromethane and washed with 50 mL water, dried (MgSO₄) and evaporated to give the O-alkylated product which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate in 65% yield.

Case 2: using cesium carbonate 

A mixture of the phenol (0.0054 mol), aliphatic bromide (0.01 mol) and cesium carbonate (0.01 mol) in 30 mL anhydrous DMF was heated at 70 ^oC for 12 h. The reaction mixture was diluted with 50 mL ethyl acetate (to precipitate out maximum dissolved cesium carbonate), filtered, washed the precipitate with ethyl acetate, the combined filtrate and washings were washed with 500 mL water (to remove DMF), dried (MgSO₄) and evaporated to give the O-alkylated product which was purified by silica gel chromatography using a gradient of hexane and ethyl acetate in 95% yield.

Case 3: selective O-alkylation of phenol in the presence of an aliphatic OH group

A mixture of the phenol containing an aliphatic OH group (0.0012 mol) and potassium carbonate (0.0012 mol) in 5 mL acetone was heated at 65 ^oC for 2 h. The reaction mixture was cooled to room temperature and added drop wise the aliphatic bromide in 5 mL acetone. The resulting mixture was stirred for overnight (12 h) at room temperature. The reaction mixture was filtered, washed the precipitate with acetone and the combined filtrate and washings was evaporated. The residue was diluted with dichloromethane and washed with water, dried (MgSO₄) and evaporated to give the O-alkylated phenol with the aliphatic OH group which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate in 97% yield.

HCl salt to free base: 

To a stirred suspension of the amine HCl salt (0.2 mol) in dichloromethane was added  aqueous solution of NaHCO₃ (0.4 mol) in 300 mL water. The mixture was stirred for 30 minutes at room temperature until it became a clear solution. The organic layer was separated, dried (Na₂SO₄) and evaporated. To recover more product from the aqueous layer it was saturated with sodium chloride, 500 mL dichloromethane was added and stirred at room temperature for overnight (12 h) to give the corresponding amine in a total of 92% yield.

Free base to HCl salt:

To a solution of the amine (0.001 mol) in 2 mL dichloromethane was added 4 mL 2M HCl solution in diethyl ether. The mixture was stirred at room temperature for 10 minutes. The solvent was evaporated, residue was triturated with ether, and solid precipitated was filtered, washed with ether and dried to give the corresponding HCl salt in 70% yield.

Another example:

Reference: US Patent 5,324,732 (a great ref. for many kind of salt preparation)

To a stirred suspension of the N-benzyl derivative (x gm, 0.01 mol) and 10% Pd-C (x gm, equal weight, introduced into the flask after evacuating and then filling it with nitrogen, keep fire extinguisher nearby in case it catches fire) in 40 mL anhydrous methanol (first introduce Pd-C, evacuate the flask, fill in nitrogen, then add methanol slowly for safety reasons) taken in a round bottom flask fitted with a wide condenser (to prevent it from blocking with formaldehyde polymer) and nitrogen inlet was added ammonium formate (0.079 mol) in one portion at room temperature. The resulting mixture was stirred at reflux for 2 h. The catalyst was filtered through a celite pad, washed with 2 × 10 mL methanol (taking care that the catalyst is never dry otherwise it may catch fire, after filtration put the Pd-C in water in a container for proper disposal). The combined filtrate and washing was evaporated under reduced pressure to give the corresponding amine in quantitative yield.

References:

Formic acid as the hydrogen source:

1. ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G. E. J. Org. Chem. 1979, 44, 3442-3444.

Ammonium formate as the hydrogen source:

2. Ram, S.; Spicer, L. D. Synth. Commun. 1987, 17, 415-418.

3. Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515-516.

Note: Please read http://curlyarrow.blogspot.com/2008/02/catalytic-hydrogenation-now-fire-free.html and the comments there in if you are planning to use Pd-C in your reaction.

To a stirred solution of the N-BOC derivative (0.01 mol) in 25 mL dichloromethane (in a round bottomed flask fitted with a gas bubbler since a gas is evolved) at room temperature was added 25 mL trifluoroacetic acid. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was evaporated below 50 ^oC and then poured to premixed solid sodium bicarbonate with few pieces of ice, extracted with dichloromethane, dried (Na₂SO₄) and evaporated to give the corresponding amine in quantitative yield.

Note:

1. We observed hydrolysis of sulfonamide group while trying to deprotect O-BOC using TFA.

2. We observed hydrolysis of ester group while trying to deprotect N-BOC using TFA.

Case 1 (where the amine is nucleophilic, example-piperazine):

To a stirred suspension of the amine with a phenolic OH group (0.01 mol) in 20 mL tetrahydrofuran (in a round bottom flask fitted with a gas bubbler) was added a solution of di-tert-butylcarbonate (0.012 mol) in 10 mL tetrahydrofuran at room temperature. Soon it became a clear solution and a gas was evolved. The resulting mixture was heated at 60 ^oC for 6 h. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water, dried (Na₂SO₄) and evaporated to give the corresponding BOC protected amine (with phenolic OH group) which was purified by triturating with hexanes (white solid, 92% yield).

Case 2 (where the amine is not nucleophilic, example-benzimidazole):

To a suspension of the amine containing phenolic OH group (0.001 mol) in 30 mL DMF was added triethylamine (0.001 mol) followed by di-tert-butyldicarbonate (0.001 mol) in 10 mL DMF followed by 4-(dimethylamino)pyridine (DMAP) (0.001 mol). The solution became clear after the addition of DMAP and a gas was evolved. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with 100 mL water, the white solid (product) precipitated was filtered, washed with water and hexanes, dried under suction to give the corresponding BOC protected amine with the free phenolic OH group (white solid, 100%).

Case 1: using aluminium chloride and ethanethiol 

To a solution of the aromatic methyl ether (0.02 mol) in 40 mL dichloromethane and 40 mL ethanethiol cooled in a ice-salt bath was added aluminum chloride (0.06 mol) portion wise (Caution-exothermic). The resulting mixture was stirred at room temperature for two days (48 h). The reaction mixture was diluted with 250 mL of dichloromethane and washed with 250 mL saturated NaHCO₃ solution, dried (Na₂SO₄) and evaporated under reduced pressure to give the corresponding phenol which was purified by silica gel column chromatography using a gradient of hexane and ethylacetate (colorless oil, 98% yield).

Reference:

1. Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem. 1980, 45, 4275-4277.

2. US Patent 2006/0052463 A1 (AlCl3 as O-demethylating agent)

3. http://lego.chemistry.tripod.com/various/demethylation.html

Note: 2-(Diethylamino)ethanethiol has been used for the odorless deprotection of aromatic methyl ethers. Magano, J.; Chen, M. H.; Clark, J. D.; Nussbaumer, T. J. Org. Chem. 2006, 71, 7103-7105.

Case 2: using sodium ethanethiolate (suitable for pyridines)

To a solution of the aromatic methyl ether (0.006 mol) in 10 mL DMF in a sealed tube at room temperature was added sodium ethanethiolate (0.03 mol). The resulting mixture was heated at 50 ^oC for 2 h. The reaction mixture was diluted with 100 mL water, and the pH was adjusted to 7 by adding 8 mL of saturated aqueous citric acid solution. Solid NaCl was added to the above solution until saturation and then extracted with dichloromethane (3 × 250 mL). The combined organic layers was evaporated, the residual oil was triturated with ether to give the corresponding phenol (white solid, 46% yield).

Reference:

1. Li, A. et. al. Tetrahedron 2003, 59, 5737-5741.

2. Lal, K. et. al. J. Org. Chem. 1987, 52, 1072-1078.

Note: We observed cleavage of aromatic-S-alkyl linkage in the substrate to aromatic-SH group while using EtSNa for O-demethylation.