High-yielding synthesis of MDA from MDP2P

High-yielding synthesis of MDA from MDP2P

by Sonson

This route to MDA isn’t anything new. In fact it has been around since 1955. The general overview of the reaction is; 1) Formation of the oxime and 2) reduction of the oxime to the amine. The fist step is easily accomplished by reacting the parent ketone with hydroxylamine hydrochloride. Old geezer Shulgin did this with pyridine[1] in a 51% yield. But it can be done with considerably better yields employing plain sodium acetate and methanol[2].

I heard the following through my friends appartment wall…

Step 1. Formation of the oxime.

5.4g sodium acetate trihydrate and 4ml water was combined in a 50ml round-bottomed flask. The mixture was heated gently with stirring until the acetate was in solution. 20 ml MeOH was added followed with 4.5g MDP2P. To this there was added 2.3g hydroxylamine hydrochloride and the mixture was refluxed with stirring for 1.5h. After this period 10ml water was added and the heating source was removed and the mixture was allowed to cool in a waterbath with the stirring continued. After returning to room temp the flask was put in the freezer for an hour or so. The white crystalline material was filtered and washed with 50ml water (the filtrate may turn cloudy as small amounts of product crystallizes). The product was dried over magnesium perchlorate. Final weight was 4.5g (92%). Mp: 84-85°C. Litt: 84-87°C (H2O-EtOH)

The oxime can also be made in equally good yields with sodium carbonate as the base in 60% EtOH [3].

The reduction is done with sodium metal in EtOH[2,4]:

Step 2. Reduction of the oxime.

3.86g (0.02 mole) oxime was dissolved in 50 ml dry ethanol (fresh 99.5% is OK, otherwise look in Vogel for a procedure for making anhydrous EtOH with Mg and I2) in a two-necked 250ml roundbottomed flask equipped with a condenser, a cork and a stirring magnet. The reaction mixture was heated to reflux, the heat was turned off and 5g elemental sodium was added in such rate that a steady reflux was maintained (make 20-30 pieces and store under hexane). The first additions is conviently kept small. (NOTE: Hydrogen evolution). At the end the reaction was slower so the heating mantle was turned back on to speed things up. The waterwhite, clear postrxn mixture was then slowly treated with 16g H2SO4 in 200ml cold water. The EtOH was removed under vacuum, and the resulting water phase was washed twice with DCM. The aq. phase was made basic by addition of 25% NaOH. The freebase was extracted with 3x30ml DCM. The pooled organic extracts was evaporated under vacuum to constant weight leaving a pale colored residue (3.36g, 94%).

The freebase was dissolved in 20ml IPA, neutralized with 1.6ml HCl and percipitated by the addition of 40 ml Et2O. The crystals was filtered and washed with a small amount of Et2O. Yield: 3.4g of white MDA-HCl. Mp 187.5-188.5°C. (Litt: 187-188°C)

This reduction can also be done in n-BuOH according to [5], and with quite a few NaBH4 reduction systems (NiCl2[6], TiCl4[7], MoO3[8], Co-PC[9], amberlyst-15+LiCl[10], and even with plain NaBH4 in EtOH according to [11]). Adding NaOH to a suspension of Ni-Al is also said to reduce oximes[12] as is SnCl2-Sn-HCl[13].

Different synthesis of oximes starting with nitroalkenes should be looked into, as this could be a good alternative to the existing methods for reducing nitroalkenes. SnCl2 reduces nitroalkenes to oximes under both acidic and basic conditions[14, 15, 16). Zn(BH4)2 in 1,2-DiMeO-ethane does reduce 3,4-MD-phenyl-2-nitropropene to the oxime in good yields [17]. Another promising route is the use of Pb in DMF [18]. This seems to reduce most nitroalkenes to the corresponding oximes.

References:

1. J. Pharm. Sci. 69; 2; 1980; 192-195
2. CA 1955;10595
3. Chem. Ber. 114;12;1981;3813-3830
4. J. Chem. Soc. Perkin. Trans. 2;2;1997;249-256
5. JACS 56; 1934; 487
6. Chem. Pharm. Bull. 36;1988;1529-1533
7. Synthesis 9;1980;695-697
8. Chem. Ber. 117;2;1984;856-858
9. Angew. Chem. 93;5;1981;477-479
10. Syn. Lett. 4;1999;409-410
11. J. Chem. Soc. Perkin. Trans. 2; 1980; pp83-86 (very sparse information)
12. Aust. J. Chem 34; 1;1981;45-56
13. JACS 67;1945;496
14. Tetr. Lett. 26;49;1985;6013-6014
15. Synth. Commun. 18;7;1988;693-698
16. Heterocycles 24;9;1986; 2581-2586
17. Tetrahedron 48;25;1992; 5317-5322
18. Tetrahedron 48;21;1992; 3313-26 among others

Reduction of Nitriles and Oximes with Na/n-Butanol (Ref 5)

The usefulness of n-butyl alcohol in the sodium reduction of a number of aliphatic cyanides and oximes has been investigated. In a considerable number of preliminary experiments upon the reduction of n-butyl cyanide it was found that: (1) better results were obtained by adding the sodium to the boiling solution of the cyanide than by adding the cyanide solution to the sodium; (2) if the temperature of the reaction mixture were kept below the boiling point mechanical stirring increased the yield of amine, but it was of no advantage to stir the refluxing solution; (3) the use of more than 7 atoms of sodium per mole of cyanide did not appreciably increase the yield of amine; and (4) all of the sodium dissolves within a convenient time if slightly more than 3 moles of n-butyl alcohol is used per atom of sodium. It is probable that (3) would not be true for all reductions of this type. The yields of amines from a series of methyl alkyl ketoximes varied from 69 to 86% of the theoretical amounts. Heptaldoxime gave 69% of the amine. n-Butyl and n-amyl cyanide gave 86 and 78%, respectively, of the corresponding amines.

Procedure

A solution of 1 mole of cyanide or oxime in 2300 cc. of n-butyl alcohol in a 5-liter two-necked flask fitted with a reflux condenser was heated to boiling and 161 g. (7 moles) of sodium added in 10-20 g. pieces at short intervals through the large neck of the flask. This required from ten to fifteen minutes. After the reaction had moderated the mixture was refluxed until practically all of the sodium had dissolved. The reaction mixture was allowed to cool, 1.5 liters of water added and the mixture distilled to remove the amine and alcohol. More water was added as necessary. The distillate was made slightly acid with hydrochloric acid and distilled to a volume of 300 ml, 500 ml of water added and distillation continued until no more alcohol came over. The water solution of amine hydrochloride was saturated with sodium hydroxide, the upper oily layer of amine separated and further dried over sodium hydroxide and then over sodium. The amine was now distilled from sodium in a 250ml special Claisen flask. If the amine is properly dried there is very little forerun and no high boiling residue.

Reference: JACS 56, 487 (1934)