N-Methyl-£-toluenesulfonamide

Cyclohexanecarbonyl chloride EK Triethylamine MCB, EK N-Methyl-A -nitroso-p-toluenesulfonamide A Isophorone MCB, A d < -Octalone-2 (Chapter 9, Section III)... 

Materials. Ketene was synthesized as described by Andreades and Carlson ( ) from diketene. Diazomethane was synthesized from N-methyl-N-nitroso-pi-toluenesulfonamide as outlined by Hudlicky (10). A typical synthesis of cyclopropanone involved the slow addition of 400 mL of a 1.0 M diethyl ether solution diazomethane to a 2-3-fold molar excess of ketene at -78°C. This synthesis was based on the... 

N-Methyb/>-toluenesulfonamide, 34, 97 /3-Methyl-S-valerolactone, 35, 87 Methyl vinyl ether, 34, 29 Methyl vinyl ketone, 37, 19 Michael condensation between 3-nitropro-pane and methyl acrylate, 32, 86 Monochlorourea, 30, 24, 25, 26 Monoethanolamine, 32, 19 Monoethyl malonate, 37, 34 Mucobromic acid, 32, 95... 

NITRO-, DIACETATE, 36, 58 -Toluenesulfenyl CHLORIDE, 35, 99 -ToLUENESULFINYL CHLORIDE, 34, 93 -Toluenesulfonamide, N-methyl-N-nitroso-, 34, 24, 96 -Tolucnesulfonic acid, 30, 30, 31 monohydrate, 36, 92 -ToLUENESULFONIC ANHYDRIDE, 36, 91 -Toluenesulfonylanthranilic acid, 32, 8, 11... 

Struempel M, Ondruschka B, Stark A (2009) Continuous production of the diazomethane precursor N-methyl-N-nitroso-p-toluenesulfonamide batch optimization and transfer into a microreactor setup. Org Process Res Dev 13(5) 1014—1021... 

Diazomethane was prepared by the method described (de Boer, Th. J. Backer, H. J. Org. Synth., Coll. Vol. IV 963, 250) using a special diazomethane generator, which can be purchased from Aldrich Chemiceil Company, Inc. (Diazald kit 210,025-0). The diazomethane solution was prepared by slow distillation of a reaction mixture, which was prepared by adding first a solution of 21.5 g of N-methyl-N-nitroso-p-toluenesulfonamide dissolved in 200 mL of ether to a solution of 6 g of potassium hydroxide, 10 mL of water, 35 mL of 2-(2-ethoxyethoxy)ethanol and 10 mL of ether, followed by a final addition of about 30 mL of ether until the distillate was colorless. All operations involving diazomethane... 

Diazomethane is generated by the reaction of aqueous NaOH with N-methyl-N-nitroso-p-toluenesulfonamide (Diazald ) in DMSO. The diazomethane is generated quantitatively and is removed by a stream of N2 into a packed column containing a stream of mixed anhydride formed from an N-protected (BOC or CBZ) amino acid and ethyl chloroformate. The diazoketone is converted to the chloroketone using HCI, as shown in Scheme 11.10. The chiral epoxide can then be formed via diastereoselective reduction with NaBH4 and treatment with base. 

Various N-nitroso-N-alkyl compounds undergo elimination to give diazoalkanes.441 One of the most convenient methods for the preparation of diazomethane involves base treatment of N-nitroso-N-methyl-p-toluenesulfonamide (illustrated above, with R = H).442 However, other compounds commonly used are (base treatment is required in all cases) ... 

Selective removal of the terf-butyldimethysilyl group from 228 to give 230, and oxidation with peroxy acid, gave mainly the epoxide (231). Treatment of 231 with N-methyl-p-toluenesulfonamide gave 232 (hav-... 

Scheme 39 Reagents (i) Diazald (N-methyl-N-nitroso-p-toluenesulfonamide).

The residue after evaporation is dissolved in 5 ml of methanol and 15 ml of diethyl ether (free of stabilizer) is added. Diazomethane is added to the resulting solution under a stream of nitrogen. (The reaction should be conducted in a well-ventilated hood.) The diazomethane is conveniently prepared from N-methyl-N-nitroso-p-toluenesulfonamide (Merck-Schuchardt, Aldrich, Fisher, Fluka, and others) in a special reaction flask as described by Schlenk and Gellerman (1960). 

S)-Tetrahydro-l -methyl-3,3-diphenyl-1 H,3H-pyrrolo[1,2-c][1,3,2]oxazabo-role was prepared from (S)-proline in two steps according to the literature procedure4 and purified by bulb-to-bulb distillation (170°C, 0.2 mm). The enantiomeric purity of the intermediate, (S)-a,a-diphenyl-2-pyrrolidinemethanol, was determined to be 99% ee by chiral HPLC analysis of its corresponding N-p-toluenesulfonamide derivative (DIACEL Chiralcel OD column hexane/ethanol, 92/8 1.0 mLVmin Rt(S) 8.6 min Rt(R) 12.8 min). The checkers used the crystalline p-methyloxazaborolidineborane complex (1.84 g, 6.34 mmol) as the catalyst. 

The reaction of a carboxylic acid with diazomethane is mild and efficient Diazomethane is usually prepared by reaction of potassium hydroxide with N-methyl-A/-nitroso-p-toluenesulfonamide (HAZARD carcinogenic) and used in ether solution since it is volatile, toxic, and explosive.44 Therefore, the method is most suitable for small scale reactions. A useful feature of the reaction is that diazomethane is intensely yellow and the consumption of the reagent is easily detected by the disappearance of the colour. It may be convenient to prepare the diazomethane in situ 45 (Trimethylsilyl)diazomethane is a safer alternative to diazomethane for the preparation of methyl esters and it is commercially available as a 2.0 M solution in hexanes,46 47... 

The following procedure has been used by Hartmann (1963) to prepare alcohol-free C-diazomethane in about 60-65% yield. N-Methyl-C -N-nitroso-p-toluenesulfonamide (22 mg, 0.103 mmole, 0.1 mC of C " ) was dissolved in 1 ml of anhydrous, peroxide-free diethyl ether in a 5-ml distilling flask fitted with a gas inlet tube. The side arm was bent vertically downward near the top and connected through a two-holed rubber stopper to a 10-ml Erlenmeyer flask. A tube from the second hole led to the back of the hood. The latter flask was cooled in a Dry-Ice-Cellosolve bath. With the reaction flask at room temperature, 1 ml of a solution of 10 mg of sodium metal in dry n-octyl alcohol was added all at once. The gas inlet tube was immediately connected and a slow stream of dry nitrogen was passed through the system. The temperature of the mixture was then raised to 70°C in an oil bath and the C-diazomethane was flushed into the cooled collection flask for about 15 min. A further 1 ml of ether was then added through the gas inlet tube and collection was continued until the distillation of the ether was complete. Use of C-dia-zomethane represents the most general method for the introduction of radioactivity into a haloketone. 

The best known and most widely used diazoalkane is diazomethane (95 equation 39). Preparative methods for diazomethane involve, in general, the nitrosation of a methylamine derivative (93), followed by cleavage under alkaline conditions. Methylamine derivatives used have included the urethanes, ureas,carboxamides, sulfonamides, guanidines and even the methylamine adducts of unsaturated ketones and sulfones. N-nitroso-N-methyl p-toluenesulfonamide (Diazald, Aldrich) is currently the most commonly used diazomethane precursor. Diazomethane is both toxic and explosive. Although in the past it has been purified by codistillation with ether, it is now usually generated, stored and used as an ether solution without distillation. 

N-Methyl-J>-toluenesulfonamide, 34,97 N-Methyl-f -toluidine, 38, 31 Methyl Jktolyl sulfone, 38, 62... 

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