Synthesis and Reduction of Azides

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One-pot Conversion of Azides to N-monomethylamines [1]

This reference is a significant advance in alkylazide reduction techniques because it reduces the azide and methylates it in one single step. This is the only ref I am aware of which yields a N-methylamine or N-ethylamine directly from the azide precursor without using catalytic hydrogenation for the reduction.

Sample procedure

Secondary alkylazide (0.148mmol) in CH2Cl2 (1.5ml) was added a solution of (CH3)3P in toluene (1.0M, .3mL) at room temp. After stirring for 1.5hr, paraformaldehyde(22.6mg, 0.753mmol) was added. The rxn. mixture was stirred for an additional 6hr at room temp then rxn was cooled to 0'C and MeOH (2.0ml) and NaBH4(28mg, 0.74mmol) was added. After stirring for .5hr the rxn. was stopped with saturated aq. NaHCO3and extracted with 5 X 10ml CH2Cl2. Extracts were pooled and evaporate to yield 83% N-methylamine.

Synthesis of Azides from Alkyl Halides in DMSO [2]

A stock solution of 0.5 M NaN3 in DMSO was prepared by stirring the solution for 24 hours at 25°C.

To a 100 ml round-bottom flask equipped with a magnetic stir bar, was added a 0.5M solution of NaN3 (0.715g, 11mmol) in DMSO (22mL) at 25°C. To this solution was added alkyl halide (10mmol), and the mixture was stirred untill all the starting material had been consumed, as observed by GC analyses. The reaction was quenched with H2O (50mL) [slightly exothermic] and stirred until it cooled to r.t. The reaction was extracted with Et2O(3x30mL); the Et2O extracts were washed with H2O (2x50mL) and once with brine (50mL). The organic layer was dried (MgSO4) filtered, and the solvent removed under vacuo(20 Torr) to afford the pure alkyl azide in almost quantitative yield.

Another variation of this reaction (cyclohexyl-azide from its tosylate) uses DMF as the solvent and with conventional heating (12h, 90°C) they isolate 91%, and with irradiation in a microwave oven (1000W, 5 min) they manage to push that even further, to 92%. Ref: Bull. Korean Chem. Soc. 24(2), 253-255 (2003)

Reduction of Azides using Aqueous CoCl2/NaBH4 [3]

Reduction of azides to amines and amides was carried out with NaBH4/CoCl2·6 H2O in sole water at 25°C under catalytic heterogeneous conditions. A broad spectrum of azides was reduced in a short time, chemoselectively in high yield and purity.

To a mixture of azide (2.0 mmol) and CoCl2*6H20 (0.048 g, 0.2mmol), and when necessary CTABr(*) (0.07g, 0.2mmol) at 25°C was added dropwise under stirring a solution of NaBH4 (0.152g, 4.0 mmol) in H2O (4mL). The formation of a black precipitate indicated the formation of a cobalt boride species. The mixture was stirred at 25°C for more than 10min when necessary. At the end of the reaction the mixture was extracted with Et2O (5x10 mL). The organic phase was dried (NaSO4) and concentrated under reduced pressure to give the pure amine or amide.

* A PTC was used in case the azide substrate was highly hydrophobic, to allow the reaction to proceed faster

Re-use of Reducing agent

The pH of the remaining mother liquor (aprox 4ml) after extraction with Et2O of amine or amide was adjusted to 8.0 by adding a few drops of concd HCl. Azide (2.0mmol) was then added followed by NaBH4 (0.152 g, 4.0 mmol) in small doses. Mixture was stirred at 25C for more than 10 min when necessary and then extracted with Et2O. The mother liquor can continue to be reused.

Reductive Acylation Of Azides Using AlI3 And Ac2O [4]

A freshly prepared solution of 1.3 g AlI3 (prepared by refluxing 1.2 g aluminium foil and 17 g iodine in 40mL dry acetonitrile till color of the solution became pale yellow) in acetonitrile was added to a refluxing solution of phenyl azide (1.3 g, 14.24 mmol) and acetic anhydride (2 mL) in acetonitrile (2 mL) and allowed to reflux until completion while monitoring the reaction by TLC (Primary Azides 30 min, Secondary 60 min, sterically hindered 90 min). The temperature of the reaction mixture was allowed to cool down to RT, and diluted with CHCl3 (10mL), washed successively with aqueous Na2S2O3 solution (20mL) and brine. The organic layer was separated, dried (over Na2SO4) and evaporated to get the crude which was purified by column chromatography (EtOAc/hexane 3:2). Yields 70-90%.

Although AlI3 is an established ether cleaving agent, the AlI3–acetic anhydride combination is found to have little effect on ether and ester functionalities under this reaction condition. Therefore this method carries the preferences to the existing ones for being mild, selective and cheap. This method provides a straightforward procedure for conversion of azides to their corresponding acetamides in excellent yield avoiding amino reduction and carboxyl activation usually required for two steps conversion.


[1] Synlett 1003-1005 (2001)
[2] Synthesis 413 (1997)
[3] Synthesis 646 (2000)
[4] Syn Comm 32(23), pp. 3625–3628 (2002)