1-Bromo-2-naphthaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized using the same procedure employed for Example 370 (1), but with 3-bromobenzaldehyde as the starting material instead of 1-bromo-2-naphthaldehyde. The product was obtained as a colorless oil (320 mg, 82%).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 1-bromo-2-naphthaldehyde (502 mg, 2.14 mmol), sodium carbonate (270 mg, 2.55 mmol), and phenylboronic acid (339 mg, 2.78 mmol) in 4.2 mL of N,N-dimethylformamide/water (2:1) was added palladium acetate (24 mg, 0.11 mmol) under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered. The filtrate was diluted with diethyl ether, and the solution was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 85/15) to obtain the title compound as a white powder (416 mg, 84%). the reaction mixture was filtered The filtrate was diluted with diethyl ether the solution was washed with brine dried over MgSO4 After filtration the filtrate was concentrated in vacuo the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 85/15)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-2-naphthaldehyde (0.740 g, 0.001 mole) in tetrahydofuran (10 mL) was added triethylamine (0.150 mL, 0.001 mole) followed by diethylphosphite (0.330 mL, 0.002 mole). The reaction mixture was then stirred at room temperature under nitrogen gas for 18 hours. The volatiles then evaporated in vacuo and further dried under vacuum. The resulting solid was triturated with ether and the solid that separated out was collected and dried under vaccum to get 0.935 g of [(1-bromonaphthalene-2-yl)-hydroxymethyl]phosphonic acid diethyl ester The volatiles then evaporated in vacuo further dried under vacuum The resulting solid was triturated with ether the solid that separated out was collected dried under vaccum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-2-naphthaldehyde (2.12 g, 8.91 mmol) in MeOH under N2 at 0° C. was treated with NaBH4 (0.51 g, 13.4 mmol), stirred for 15 minutes, quenched with acetone, and concentrated. Purification on silica gel with 5% ethyl acetate/CH2Cl2 provided 1.95 g (92%) of the desired compound as a white solid. quenched with acetone concentrated Purification on silica gel with 5% ethyl acetate/CH2Cl2

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (methoxymethyl)triphenyl phosphonium chloride (32.0 g, 93.3 mmol) in THF (100 mL) at −78° C. was treated with potasium tert-butoxide (9.90 g, 88.1 mmol), stirred cold for 1 hour, treated with a solution of 1-bromo-2-naphthaldehyde (12.1 g, 51.7 mmol) (commercially available from TCI America) in THF (75 mL) over 15 minutes, stirred for 16 hours at room temperature, treated with aqueous ammonium chloride (200 mL) and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4), filtered, and concentrated to an oil. The oil was purified on silica gel with a gradient of 2% to 5% ethyl acetate/hexanes to provide 11.8 g (87%) of the desired compound. stirred for 16 hours at room temperature extracted with ethyl acetate The ethyl acetate was washed with brine dried (MgSO4) filtered concentrated to an oil The oil was purified on silica gel with a gradient of 2% to 5% ethyl acetate/hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Scheme 3 also shows a general synthetic route to compounds of formula I. Reaction of 1-bromo-2-naphthaldehyde with sodium borohydride provided 1-bromo-2-naphthalenemethanol (xiv). Alcohol (xiv) was reacted with BOC-protected sulfonamide (xc), triphenylphosphine and diethyl azodicarboxylate to provide sulfonamide (xv). The sulfonamide was reacted with tert-butyllithium at a temperature between about -90° C. and about 10° C. in THF to provide (xvi). The nitrogen of compound (xvi) was protected as the benzyl carbamate by treating (xvi) with sodium hydride and benzylchloroformate, and the tert-butyl ester was then hydrolyzed with trifluoroacetic acid to provide carboxylic acid (xvii). The carboxylic acid (xvii) was converted to the hydroxamate (xviii) following the procedure outlined in Scheme 1. Hydrogenation of (xvii) in the prescence of a palladium catalyst provided a compound of formula I.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 38.4 g (0.164 mole) 1-bromo-2-naphthaldehyde, 16.4g (0.164 mole) triethylamine, and 30.6 g (0.164 mole) of 2-amino-1-phenyl-1-propanol hydrochloride in 500 ml CH3OH was stirred and refluxed for 60 minutes, then cooled to 10°-20° while 6.23 g (0.164 mole) of sodium borohydride was added over 5 minutes. The reaction mixture was stirred at ambient temperature (15°-21°) for 60 minutes and diluted with 500 ml H2O. The mixture was stirred for 15 minutes and extracted with 2 × 350 ml CHCl3. The combined extracts were dried (MgSO4) and concentrated to dryness in vacuo to give 59.6 g (99%) of the free base. refluxed for 60 minutes was added over 5 minutes The reaction mixture was stirred at ambient temperature (15°-21°) for 60 minutes The mixture was stirred for 15 minutes extracted with 2 × 350 ml CHCl3 The combined extracts were dried (MgSO4) concentrated to dryness in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-2-naphthaldehyde (0.740 g, 0.001 mole) in tetrahydrofuran (10 mL) was added triethylamine (0.150 mL, 0.001 mole) followed by diethylphosphite (0.330 mL, 0.002 mole). The reaction mixture was then stirred at room temperature under nitrogen gas for 18 hours. The volatiles then evaporated in vacuo and further dried under vacuum. The resulting solid was triturated with ether and the solid that separated out was collected and dried under vacuum to get 0.935 g of [(1-bromonaphthalene-2-yl)-hydroxymethyl]phosphonic acid diethyl ester B. This material was added to 40 mL of acetone. 20 eq. of manganese dioxide (4.31 g, 0.05 moles) was added and the mixture was stirred at room temperature for one hour. Another 20 eq. of manganese dioxide was added to it and it was stirred for another one hour. The solid manganese dioxide was filtered off on a Celite® pad and washed with hot acetone. Combined filtrates were evaporated to afford 0.6 g of crude (1-bromo-naphthalene-2-carbony)phosphonic acid diethyl ester. Flash chromatography on silica gel using 0-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.260 g of intermediate. C. To a solution of diethyl (1-bromonaphthalene-2-carbony)phosphonate ester in dichloromethane (2 mL) was added (diethylamino)sulfur trifluoride (1.3 mL, 0.01 mole) at 0° C. and it was allowed to come to room temperature then stirred for another 4 hours. The reaction mixture then was diluted with dichloromethane (50 mL) and washed with cold saturated aqueous sodium bicarbonate (NaHCO3, 25 mL), then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided 0.260 g of product. Flash chromatography on silica gel using 0-5% EtOAc/dichloromethane followed by drying of the product under high vacuum afforded 0.120 g of diethyl [(1-bromo-naphthalene-2-yl)difluoromethylphosphonate ester. Compound 80 was prepared from this corresponding diethyl ester using procedures similar to those of Example 40. 1H NMR: (DMSO-d6, 400 MHz) δ 8.52 (d, 1H, J=8.4 Hz) 8.11 (m, 2H), 7.79 (m, 3H). MS (ion spray): m/z 337.00 (M+H) The volatiles then evaporated in vacuo further dried under vacuum The resulting solid was triturated with ether the solid that separated out was collected dried under vacuum