PMGB

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.  

To a stirred solution of alkylmagnesium bromide (2M solution in ether, 0.039 mol) under nitrogen atmosphere was added drop wise the nitrile (0.026 mol) in 20 mL anhydrous THF at 40 ^oC (exothermic- gentle reflux observed). Then the reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and then added drop wise to stirred slurry of sodium borohydride in 20 mL isopropanol (caution-exothermic). The resulting mixture was refluxed for overnight (12 h). The reaction mixture was evaporated; the residue was diluted with dichloromethane, washed with saturated aq. NaHCO₃ solution, dried (Na₂SO₄) and evaporated under reduced pressure to give the corresponding amine which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate (colorless oil, 75% yield).

To a stirred suspension of Cs₂CO₃ (0.006 mol) in 3 mL DMF was added the representative primary amine (0.006 mol) and the resulting mixture was stirred at room temperature for 30 minutes. Then a solution of alkyl bromide (0.002 mol) in 2 mL DMF was added over a period of 5 minutes. The resulting mixture was stirred at room temperature for overnight (12 h). The reaction mixture was filtered and the filtrate was diluted with 25 mL ethyl acetate, washed with 50 mL brine, 50 mL water and dried (Na₂SO₄), evaporated to give the corresponding secondary amine which was purified by silica gel chromatography using a gradient of hexane and ethyl acetate (colorless oil, 15%). 

To a suspension of the amine HCl salt (0.0437 mol) in 60 mL acetonitrile cooled by an ice-bath was added N,N-diisopropylethylamine (DIPEA) (0.11 mol). Aliphatic bromide (0.0437 mol) was added and the resulting mixture was stirred at room temperature for overnight (12 h). The solution became clear in the morning. The solvent was evaporated, residue was diluted with 50 mL dichloromethane, washed with 50 mL water, dried (MgSO₄) and evaporated to give the corresponding N-alkylated product which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate (colorless oil, 95% yield).

Reference: Moore, J. L.; Taylor, S. M.; Soloshonok, V. A. Arkivoc 2005, vi, 287-292.

Note: For unreactive long chain aliphatic bromides the reaction has to be heated at reflux for overnight (12 h) to get the product.

N-Benzylation:

To the amine HCl salt (0.044 mol) in 75 mL acetonitrile cooled in an ice-bath was added N,N-diisopropylethylamine (DIPEA)  (0.088 mol) followed by benzyl bromide (0.044 mol). The mixture was stirred at room temperature for overnight (12 h). The solvent was evaporated, the residue was diluted with 100 mL dichloromethane, washed with 100 mL water, dried (MgSO₄) and evaporated to give the corresponding N-benzylated product in quantitative yield.

Case 1: Esterification of an aromatic carboxylic acid  

To a suspension of the carboxylic acid (1 mol) in 120 mL anhydrous ethanol was added 1.2 mL concentrated sulfuric acid at room temperature. The resulting mixture was stirred at reflux for two days (48 h) until the suspension became a clear solution. The solvent was evaporated. The residue was diluted with dichloromethane and washed with saturated aqueous NaHCO₃ solution, dried (MgSO₄) and evaporated. The residue was triturated with ether to give the corresponding ethyl ester (white solid, 83% yield).

¹H NMR (400 MHz, CDCl₃): d 1.38 (t, J = 7.2 Hz, 3H); 2.66 (t, J = 8.0 Hz, 2H); 3.02 (t, J = 8.0 Hz, 2H); 4.37 (q, J = 7.2 Hz, 2H); 7.22 (d, J = 8.0 Hz, 1H); 7.48 (s, 1H); 7.67 (dd, J = 1.6, 8.0 Hz, 1H); 8.59 (broad s, 1H).

Case 2: Coupling of a benzylic alcohol with an aliphatic carboxylic acid

A mixture of the benzyl alcohol (0.0008 mol), aliphatic carboxylic acid (0.0008 mol), dicyclohexylcarbodiimide (DCC) (0.001 mol), 4-(dimethylamino) pyridine (DMAP) (0.001 mol) in 30 mL tetrahydrofuran was stirred at room temperature for 6 hours. The reaction mixture was evaporated; the residue was diluted with dichloromethane, and filtered to remove the white solid (dicyclohexyl urea) precipitated. The filtrate and washings was washed with saturated aqueous sodium bicarbonate solution (to remove the unreacted carboxylic acid) and water (to remove DMAP), dried (MgSO₄) and evaporated to give the corresponding ester which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate followed by triturating with ether (white solid, 50% yield).