Rhodiums Chapter

[This is a chapter written entirely by a chemist named Rhodium (with guest speaker Osmium!). Rhodium is, as far as Strike is concerned, the world's leading underground scientist. Knowledgeable in nearly every aspect of drug chemistry, this chemist has been the savior for many a person that was lost. Here he has contributed some new reactions for your reading pleasure. Radical stuff that you can bet will become the next wave of synthesis protocol. The rest of this chapter is Rhodium's voice.]

Syntheses for Total Synthesis II by Rhodium 980620

Preparation of 3,4-methylenedioxyphenyl-2-nitropropene (from piperonal)

In Pihkal, Alexander Shulgin mentions that the preparation of MDP-nitropropene can be carried out in cold methanol with aqueous sodium hydroxide as the base. In fact, this method is even more reliable, and gives higher yields than the other method advocated by the dear doctor in his book.

15g of piperonal was dissolved in 40ml of methanol under stirring in a 250ml Erlenmeyer flask. When all of the piperonal had dissolved, 7.1g nitroethane was added to the solution. The flask was put in a ice/salt-bath with magnetic stirring, and when the tem-

perature of the solution had dropped to 0°C, an ice-cold solution of 4g of NaOH in 20ml dH20 was added at such a rate that temperature never rose above 10°C. A white precipitate formed at the bottom of the flask during this addition, which was broken up with a glass rod. The stirring was continued for another hour, while the temperature of the solution was never allowed to rise above 5°C, and at the end of this time, 100 ml of ice-cold dH20 was added to the solution, which caused even more precipitation of white solid. The whole slurry was poured into 100 ml of ice-cold 2M HCI solution in a 500ml Erlenmeyer flask, which was gently swirled, and there was a slight bubbling and fizzing, with the color of the solution shifting from white to blue to green to yellow in under a minute. Quite spectacular! When the fizzing had subsided, the solution was once again placed in an ice-bath with magnetic stirring. When the temperature had dropped to about 5°C, the solution was clear with yellow granules of crude product at the bottom. The granules were filtered with suction, and recrystallized from IPA. After air-drying, the canary-yellow crystals amounted to a yield of 65-70% of theory.

This nitropropene should be used within a week, or stored in the cold, as the color fades to a slight orange over a couple of weeks in room temperature, which is a sign of decomposition.

A.I. Vogel, Practical Organic Chemistry, 5th Ed.

Preparation of Phenyl-2-Propanone (P2P)

In this preparation, phenyl-2-nitropropene is reduced to phenyl-2-nitropropane with sodium borohydride in methanol, followed by hydrolysis of the nitro group with hydrogen peroxide and potassium carbonate, a variety of the Nef reaction. The preparation is a one-pot synthesis, without isolation of the intermediate.

Phenyl-2-Nitropropene Phenyl-2-Nitropropane Phenyl-2-Propanone

Phenyl-2-Nitropropene Phenyl-2-Nitropropane Phenyl-2-Propanone

Efforts directed to prepare MDP2P via this method results in good yields of a ketone with properties completely dissimilar to MDP2P, and is probably the propiophenone, formed by migration of the nitro group during the hydrolysis.

16.3g (0.1 mole) phenyl-2-nitropropene was dissolved in 200ml methanol in a 250ml Erlenmeyer flask situated on a magnetic stirrer, and chilled to OoC with an ice/salt bath. Then, with good stirring, 7.6g (0.2 mole) of NaBH4 was added a little at the time, and the temperature was not allowed to rise above 15°C. When the generation of heat had subsided, the ice/salt-bath was removed and the solution was stirred at room temperature for two hours. At the end of this period, the flask was once again placed in an ice/salt bath and the solution was allowed to cool to 0°C again. 100 ml of 30% H202 was then added, together with 30 grams of anhydrous potassium carbonate, and the solution was left to stir for 18-24 hours at room temp. During the addition of H2O2/K2CO3 a white, sticky precipitate forms, which can be a bit too thick for a weak magnetic stirrer to handle, so the mass can be stirred with a glass rod now and then during the first two hours, after which the precipitate will be much looser and no match for any mag-stirrer. The next day, the solution is slowly acidified with 2M HCI with good stirring, care being taken for the evolution of heat and C02. About 300 ml of acid is needed. When the pH of the solution turned acid, the color became significantly more yellow, but the acidity was confirmed with pH paper. All of the precipitate was also be gone at this point. The solution was extracted with 3x100ml CH2CI2, and the pooled organic extracts washed with 100ml 2M NaOH and 200ml HzO. The organic phase was dried over MgS04, filtered with suction, and the solvent removed under vacuum to give a clear yellow oil. After distillation of said oil at aspirator vacuum, the yield was around 60-70% of phenyl-2-propanone (P2P) as a light yellow oil.

Ref: R. Ballini, Synthesis 723-726 (1994)

Preparation of Phenyl-2-Propanone oxime

Internal nitroalkenes can be reduced to the corresponding ketox-imes by SnCI2. The second method is a modification of the first, also allowing terminal nitroalkenes (such as nitrostyrenes) to be reduced to aldoximes. The oximes, in turn, can either be reduced to the corresponding amines, or cleaved to form the carbonyl compound.

Phenyl-2-Nitropropene Phenyl-2-Propanone Oxime

Method 1

A sodium stannite solution was prepared by addition of aqueous sodium hydroxide (2.5 mol, 100g) to aqueous stannous chloride (0.25 mol, 56g). The initially formed precipitate redissolved to form a clear solution. This solution was gradually added to a solution of 16.3g (0.1 mol) phenyl-2-nitropropene in THF at room temperature. A slightly exothermic reaction ensued, and the reaction mixture was stirred for 30 min, a saturated sodium chloride solution was added, and the solution was extracted with ether and the pooled extracts were evaporated under vacuum to give essentially pure P2P oxime in 80% yield.

Method 2

16.3g (0.1 mol) Phenyl-2-nitropropene and 45g (0.2 mol) of stannous chloride dihydrate (SnCI2*2H20) was dissolved under stirring in 200ml ethyl acetate in a 250ml beaker, and the slightly exo-

thermic reaction was allowed to run its course. When the reaction mixture again had cooled to room temperature, it was poured on 200g of an ice/water mix, and was made slightly basic (pH 7-8) with 5% NaHC03. The product was extracted into ether, washed with a saturated NaCI solution, dried over Na2S04 and the solvent removed under vacuum to give almost pure P2P oxime in 90-95% yield.

Cleavage of Oximes The classic way of cleaving an oxime to the corresponding carbonyl compound is through acid hydrolysis, or an acid catalyzed exchange reaction with excess formaldehyde. This is a crude method, and has often non-satisfactory yields. Below is a very good alternative method, using sodium bisulfite. Alkaline H202 can also be used, as in Synth Comm 10(6), 465-468 (1980).

Phenyl-2-Propanone Oxime

Phenyl-2-Propanone

Oxime Cleavage with Sodium Bisulfite

14.9 grams of P2P oxime (0.1 mol) is dissolved in 150ml 50% alcohol and is refluxed with grams 36.4 grams (0.35 mol) sodium bisulfite for 6 hours, when the reaction had gone to completion. The ethanol was removed under vacuum, and the residue mixed with 25ml DCM and the mixture was treated with an excess of 2M HCI and stirred until two clear layers formed. The layers were separated, and the aqueous layer was extracted with 2x25 ml DCM, and the organic extracts were combined and the solvent evaporated to give a near quantitative yield of P2P, which, if it has an orangish tinge, can be vacuum distilled to yield a light yellow oil.

Preparation of MDP2P from safrole

Safrole can be oxidized to safrole epoxide with H202 in a two-phase system, using a quaternary phosphotungstic PTC. The formed safrole epoxide is then isomerized to MDP2P with Lil.

Safrole

MD-P2P

Safrole

MD-P2P

Preparation of the catalyst

A suspension of tungstic acid (2.50g, 10 mmol) in 7 ml of 30% aqueous H202 was stirred and heated to 60°C until a colorless solution was obtained. To this solution, filtered and cooled to room temperature, was added 40% w/v H3P04 (0.62ml, ca 2.5 mmol), and the whole was diluted to 30 ml with water. To the resultant soluton, 2.09g of methyltrioctylammonium chloride (97% pure, equiuvalent to 2.027g, 5 mmol) in DCM (40 ml) was added drop-wise with stirring over about 2 min. Stirring was continued for an additional 15 min. The organic phase was then separated, dried over Na2S04, filtered, and gently evaporated on a rotary evaporated under reduced pressure at 40-50°C (bath) to give 3.70 g (98.4%, based on the quaternary ammonium salt charged) of an almost colorless syrup.

Ref: C. Venturello, J. Org. Chem. 53, 1553-1557 (1988)

Oxidation of safrole to MDP2P

In a 100ml three-necked, round-bottomed flask equipped with mechanical stirrer, thermometer and a reflux condenser, a vigorously stirred mixture of the above catalyst (0.7g, 0.31 mmol), safrole (13.24g, 80mmol), benzene (35 ml) and 40% w/v H202 (5.10ml, 60 -169-

mmol) was heated to 60°C and kept at this temperature for 60 min (External cooling is needed!). The mixture was cooled to room temp, the organic phase was separated and diluted with 30 ml Et20. In order to remove the catalyst, the organic solution was first stirred with a solution of Na2C03 (0.75g) and Na2S03 (0.75g) in water (10 ml) for a few minutes, then separated, dried over Na2S04 and passed through a short column (2.5 cm diam) of silica gel (50g), and ~300ml anhydrous Et20 was passed through the column to ensure complete elution of the products. The solvent was evaporated and the residue dissolved in 18 ml of tetraglyme and treated with anhydrous Lil (0.130g, 0.97 mmol) at 130DC for 5h. After cooling, the products were distilled under vacuum, recovering 5.17 grams safrole (saved for the next run) and collecting 6.25 grams of MDP2P.

Ref: C. Venturello, US Pat 4,731,482 C. Venturello, Synthesis, 1229-1231 (1992)

Reduction of nitroalkenes to primary amines

NaBH4 in methanol, catalyzed by nickel boride, can be used to reduce nitroalkenes to aminoalkanes in about 70% yields in 15 min at room temp. The nickel boride is prepared in situ from NiCI2*6H20 (nickel chloride hexahydrate) and NaBH4. The method is general, and can be applied to many conjugated nitroalkenes. Other novel promising methods are catalytic transfer hydrogénation with Pd/C (Tet Lett 29(45), 5733-5734 (1988)), NaBH4 in methanol, followed by Al/Hg (Tet Lett, 1317-1320 (1977)), NaBH4 and CuS04 (Synlett 419-420 (1990)), and finally NaBH4 and tri-methylsilylchloride in THF (Angew Chem Int Ed Engl 28, 218-220 (1989))

M DA

MD-Phenyl-2-Nitropropene

M DA

Reduction with NaBH4/NiCI2

3.68 grams NiCI2*6H20 (15.5 mmol) was dissolved in 300 ml MeOH, and 1.76g NaBH4 (46.5 mmol) was added portionwise (Caution, frothing!) with stirring to the wonderfully light green solution, and the solution immediately turned black and hydrogen was evolved. The solution was left to stir at room temp for 30 minutes, and 5.0 grams (31 mmol) phenyl-2-nitropropene was added all at once, followed by 4.1 grams NaBH4 in small portions over a period of 5 minutes, care being taken for the frothing. After 15 minutes, the reaction mixture was filtered through celite to remove the boride and the filter cake was washed with 50 ml MeOH. The solvent was removed under vacuum, and the residue taken up in 100ml dilute H2S04, washed with 3x25 ml CH2CI2, basified with 25% NaOH, and extracted with 3x50 ml CH2CI2. The pooled extracts were dried over MgS04, filtered and the solvent was evaporated in vacuum, the residue dissolved in a little IPA, and 37% HCI was added until acid. The solution was then diluted with diethyl ether until turbid, and left in the freezer until all product had precipitated. The white crystals of amphetamine hydrochloride was filtered off and air dried. MDA can be produced in exactly the same fashion, just use 6.4 grams of 3,4-methylenedioxyphenyl-2-nitropropene instead of the phenyl-2-nitropropene.

Ref: Osby & Ganem, Tet Lett 26(52), 6413-6416 (1985

Proposed Synthesis of MMDA and Mescaline by Rhodium and Osmium 980519

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