(Hive Bee)
12-06-03 17:27
No 475109
(Rated as: excellent)
e.g. R = 1,4-Dimethoxy; 2-Bromo-1,4-dimethoxy; 2,6-dimethoxyphenol; 4-methoxy
e.g. * = H; CH3; C2H5
The idea behind this reaction is as follows:
1) do not use benzaldehydes as they are watched and therefore hard to get for many bees
2) avoid the use of common reducing agents like LAH and NaBH4
3) use common chemicals
4) keep the reaction as general as possible
5) provide literature references for the theoretical reaction scheme
Benzylbromides are used as benzaldehyde equivalents and nitropropionic acid esters as nitroethane equivalents.
Adding CN- to benzylbromides would yield phenylacetonitriles which can bee reduced to PEAs but there would bee no general way to the corresponding amphetamines. The use of alkali cyanides should bee avoided in general and the reduction of phenylacetonitriles is not as well established in the Hive community as the reduction of phenylnitroalkanes.
Therefore the use of 2-nitro acetic or propionic esters would be the alternative, although it would need one more step, but the decarboxylation is hardly a step itself as it is easy as synthesizing GHB.
All footnotes and italics by Lego
Step 1: Bromomethylation of benzene
With Hbr
Post 472838 (Rhodium: "Bromomethylation of 1,4-Dimethoxybenzene", Methods Discourse)
Without Hbr
Monatshefte, 1950, 917-920
111,0 dry, finely powdered NaBr is suspended in 50,0 g benzene1, 50,0 ml glacial acetic acid and 27,0 g paraformaldehyde. The mixture is stirred and heated to reflux at 80° C. Over a period of 3 h a mixture of 158,0 g sulfuric acid (d = 1,84 g/ml, 96%) and 80,0 ml glacial acetic acid is added. The mixture is stirred for further 9 h at 80° C, then for 8 h at 80° C without stirring. The reaction mixture was allowed to cool to room temperature and lots of water was added. The formed yellow oil was separated. The aqueous phase was extracted with benzene (feel free to use toluene or xylene), the organic phase and the yellow oil were pooled, treated in usual manner with water, 5% sodium carbonate solution and again with water and dried. After evaporation of solvent the oily residue was destilled at 11 torr (14,7 mbar). The boiling point was 82° C and 95,2 g pure benzylbromide were obtained. Yield: 86,5% (based on benzene).
1 The authors use the same reagent system for the 1,4-bis-bromomethylation of benzene (32,3%), p-bromomethylation of toluene (87%) and bromobenzene (35,2%) and alpha-bromomethylation of napthalene (81%). Other substituted benzenes like 1,4-dimethoxybenzene or 2,6-dimethoxyphenol should also work. Although the yields show drastic differences this should bee no problem as all reagents are very cheap and the procedure can bee performed on a large scale.
Step 2: Benzylbromide --> Methyl 2-Nitro-3-Phenylpropionate
Synth. Comm., 1987, 17(12), 1421-1429 (../rhodium/pdf /nitroacetate
Benzyl bromide (1a, 1.8 g1) was added to a stirring solution of methyl nitroacetate (2, 1.21 g) in dimethyl formamide (10 ml) containing benzyl triethyl ammonium chloride2 (TEBA, 0.009 g) and anhydrous KHCO3 (0.5 g) at room temperature.
The reaction mixture was stirred at 60 °C for 16 hrs. DMF was removed under vacuum and the mixture was diluted with water and extracted with ether. Drying and evaporation of the solvent furnished an oil which on vacuum distillation (110°-115 °C/3 mm) yielded pure (TLC) (3a, 1.49 g, Methyl 2-nitro-3-propionate).
In case of 3b and 3c purification was achieved by SiO2 chromatography using EtOAc : PhH (1:9) as eluents.
1 10,5 mmole of any other benzylbromide can bee substituted
2 For OTC phase transfer catalysts see: Post 427515 (moo: "OTC fabric softener phase transfer catalysts", Novel Discourse)
Step 3: Decarboxylation
Method A:
JACS, 1955, 77, 5747-5748
3-(2-Nitroethyl)-indole (II). A solution of sodium hydroxide (32.0 g., 0.8 mole) in 64 ml. of water was added to 78.6 g. (0.30 mole) of ethyl alpha-nitro-beta-(3-indole)-propionate ( I ) in 200 ml. of ethanol. The resulting solution was allowed to stand a t room temperature for 44 hours. Solvent was removed under reduced pressure until the flask contained a mass of solid, semi-crystalline material. Ethanol (400 ml.) was added, the mixture was slurried well and the solid was collected on a filter. It was washed with ethanol, then with ether and dried on the filter. The solid was dissolved in 600 ml. of water, the solution was cooled in ice and acidified by slowly adding 20% hydrochloric acid until the pH was between 4 and 5 . Crystalline material began to separate and the flask was cooled at 4° overnight. The light pink crystals were collected, washed with water and dried under vacuum. The yield of 3-(2-nitroethyl)-indole was 47.4 g. (83.27,). Material of analytical purity was obtained from the "practical grade" product described above by dissolving it in 200 ml. of ethanol, treating the solution with charcoal, filtering and adding 95 ml. of warm water to the warm (60°) filtrate. The flask was allowed to cool slowly to room temperature and was then placed in the refrigerator for 2 days. The large, sparkling plates were collected on a filter and washed with two 40 ml portions of 50% ethanol. The product, dried under vacuum, weighed 39.14 g. (68.5%) and melted at 55.5-56.1°. Two months later the melting point of the same material was 68.3-69.2°. It was shown by analysis and infrared spectra that these are dimorphic forms.
Method B:
J. Org. Chem., 1991, 56(16), 4990-4993
Nomenclature overkill (1.13 g, 3.08 mmol), sodium chloride (1.0 g, 17 mmol), and water (0.2 mL, 20 mmol) in dimethyl sulfoxide (15 mL) was heated at 150 °C for 4 h. The solvent was evaporated at reduced pressure, and the black residue was taken up in ethyl acetate and filtered through a small plug of Celite. The filtrate was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to leave a light brown solid. This solid was purified by silica gel chromatography using 1:1 hexanes-ethyl acetate as eluent to give the title compound ae a white solid (0.66 g, 66%).
Step 4: Reduction of the nitro group
Post 460139 (Bandil: "Formic acid reduction - comments", Methods Discourse)
Post 465461 (Bandil: "Proof of concept!", Novel Discourse)
Post 472344 (Rhodium: "Nitro to Amine Reduction - Formic Acid/Ra-Ni", Methods Discourse)
Post 353051 (foxy2: "Raney Nickel CTH Reduction of Nitro/Nitrile Groups", Methods Discourse)
Post 473449 (Rhodium: "NaBH4/BiCl3/THF: Reduction of Nitro & Imine", Novel Discourse)
Post 474130 (Lego: "Selective reduction of nitro compounds with Ti(II)", Novel Discourse)
Post 454846 (Rhodium: "Here are a few of the references located", Methods Discourse)
Post 435007 (Lego: "Zn(BH4)2/Pyridine reduces nitro compounds", Novel Discourse)
Reduction of Nitroalkanes to amines using Zinc&Ammonium Formate (../rhodium /nitro2
Reduction of Nitroalkanes to amines using Zinc&Hydrazinium Formate (../rhodium /nitro2
Reduction of nitroalkenes to nitroalkanes with 2-phenylbenzimidazoline (../rhodium /phenyl
and many, many more, UTFSE
Large-scale OTC synthesis of methyl nitroacetate
J. Org. Chem., 1963, 28, 615-617
Magnesium Methyl Carbonate.
Eight liters of anhydrous methanol was placed in a 12-1. flask equipped with a reflux condenser, stirrer, and provisions for passing gas over the liquid.
After the reaction of magnesium and methanol had been initiated using a few grams of magnesium, a total of 480 g. (20 moles) of magnesium turnings was added at a rate to maintain a constant,
but controlled, reflux. After the magnesium had completely reacted, the exceas methanol was stripped off at water pump vacuum. A 50° water bath was used to heat the mixture, and stirring was continued as long as possible to aid in removing the methanol. However, it is essential that some methanol remain
in the solid mass or redissolution becomes extremely slow. When the pressure in the system dropped to the minimum that the water pump was capable of (approximately 20 mm.), enough dimethylformamide was added to the flask to give a total volume of 10 l. Then carbon dioxide was admitted to the stirred system as rapidly as it could be taken up. A bubble counter was used at the outlet of the system to maintain a positive pressure.
After all the magnesium methoxide had dissolved, a short bubble cap fractionating column was put on the flask and the temperature was raised to distill any remaining methanol. The reaction mixture was stirred under a slow stream of carbon dioxide during this distillation. The distillation was continued until the head temperature reached approximately 150°. Then the mixture was cooled to room temperature under carbon dioxide to assure saturation.
The molarity of the solution with respect to magnesium was determined by adding a known volume to excess standard sulfuric acid, heating to dispel carbon dioxide, and back-titrating with sodium hydroxide. The carbon dioxide content of the reagent could be determined gasometrically; however, the interpretation of the result is not straightforward. A magnesium methyl carbonate solution prepared in this fashion was used for seven months with no detectable change in its effectiveness. All the methyl esters were prepared in an identical fashion. The preparation of methyl a-nitrobutyrate is given as an illustration.
Methyl a-Nitrobutyrate.
(a) Carboxylation of Nitropropane.
One liter of 2 M magnesium methyl carbonate was placed in a 2-l flask equipped with a stirrer, a gas inlet tube, and a combination condenser and gas outlet. The reagent was heated, while stirring, to 60° under a carbon dioxide stream. When the temperature of the magnesium methyl carbonate solution had stabilized a t approximately 60°, 89 g. of 1-nitropropane1 was added, and the carbon dioxide stream was replaced by a slow nitrogen stream.
After stirring for 6 hr. at 60°, the reaction mixture was cooled to 10° with an ice bath, and then either hydrolyzed or the magnesium chelate precipitated.
(b) Hydrolysis and Esterification.
The carboxylation mixture was poured with vigorous stirring into a mixture of 600 ml of concentrated hydrochloric acid and 750 g. of ice that had been overlayed with 100 ml of ether. The ether was separated and the aqueous layer extracted four times with 100-ml portions of ether. The ether extracts were combined and given a preliminary drying for 15 min. with powdered anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the drying was completed with phosphorus pentoxide. The essentially colorless ether solution was evaporated on a rotary film evaporator at room temperature or slightly below. While the ether was evaporating, 200 ml of 2 M methanolic hydrogen chloride was cooled to -50°. This was poured into the flask containing the a-nitrobutyric acid and the mixture was allowed to warm spontaneously to room temperature and stand overnight. Approximately 100 ml of the methanol was removed at room temperature, under vacuum, and the remaining reaction mixture was poured into 200 ml of water.
The aqueous solution was extracted five times with 50-ml portions of ether, the ether dried over magnesium sulfate and distilled.
The yield of methyl a-nitrobutyrate was 64.7 g. (44%), b.p. 77°/2.5, n20D 1.4249.
(c) Precipitation and Esterification.
The carboxylation mixture was poured with vigorous stirring into 2 l of ether to precipitate the magnesium chelate of a-nitrobutyric acid and unchanged magnesium methyl carbonate. After decanting the supernatant liquid phase, 1 l of methanol containing 200 g. of hydrogen chloride cooled to -50° was added to the solid precipitate. This mixture was allowed to warm spontaneously to room temperature and stand overnight. Approximately 600 ml of methanol was distilled at room temperature under vacuum, and the remaining mixture was poured into 800 ml of water. The aqueous system was extracted eight times with 50-ml portions of ether. After drying the ether solution with magnesium sulfate, the product was distilled. The yield was 67 g. (45.5%) of methyl a-nitrobutyrate.
1 89 g of 1-nitropropan are 1 mol, therefore use 61 g or 53,5 ml of nitromethane for the synthesis of methyl nitroacetate
Synthesis of 2-nitro propionic acid esters
2-bromo propionic acid esters (either methyl or ethyl) are cheap (1 l ~ 80$) and (as far as Lego knows) not watched. A simple exchange of the bromide with a nitrite will yield the desired 2-nitro propionic acid. For a more detailed discussion see Post 103078 (rev drone: "What can be done to improve the performance of clandestine nitroethane synth?", Chemistry Discourse) and Post 474617 (evil_emma: "question about Nitroethane-synths", Methods Discourse).
Alanine esters to alpha-bromoalanine esters (aka 2-bromopropionic acid esters): Post 460615 (psyloxy: "a-bromopropionic acid from alanine - 95% yield", Chemistry Discourse)
The candle that burns twice as bright burns half as long
(Hive Bee)
01-05-04 10:22
No 480535
(Rated as: good read)
Great Post, Lego!
SWIM has to try this out soon!
In Post 472838 (Rhodium: "Bromomethylation of 1,4-Dimethoxybenzene", Methods Discourse) they make the di-bromomomethylated product. So using half the amount of Paraformaldehyde and Hbr should lead to the monobromomethylated dimethoxybenzene...
The Methyl nitroacetate is somewhat hard to get, but SWIM found a very nice procedure at orgsyn.org:
Organic Syntheses, CV 6, 797
http://www.orgsyn.org/orgsyn/prep.asp?pr
Best wishes,
xicori
(Newbee)
01-06-04 00:59
No 480711
Is there any special reason for using benzyl -bromides insted -chlorides?
The chlorides are very reactive as well and the methoxy groups activate it even further. The alkylation might be optimised in a way to avoid DMF. I once used a similar synth to make 4-phenyl-butan-2-one from benzylchloride and ethyl acetoacethate. It worked in ethanol solvent and NaOH as a base with a very good yield. A similar synth to betta-phenyl-propionic acid failed presumably becasue NaOH is not basic enough to deprotonate efficiently the diehyl malonate(NaOEt is required). But acidity is not a problem with ethyl nitropropenoates.
My other question is: why everybody avoids using 4-halogen-2,5-dimethoxy-benzylchloride?
Its much easier to make than just 2,5-dimethoxy-benzylchloride as the halogen deactivate the ring, therefore inhibiting side reactions in chloromethylation reaction. Besides the Zn/HCOOH reduction does not dehalogenate the ring halogens, not even the iodine! (at least generalising on the examples checked)
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
01-10-04 01:22
No 481578
Another similar route from benzylhalogenides, though maybe longer, should be:
1.) alkylation of diethyl methylmalonate (or diethyl malonate)
2.) Hydrolysis/decarboxylation
3.) 3-aryl-(2-methyl)-propanoic acid -> 3-aryl-(2-methyl)-propanamide (maybe just heathing with urea?)
4.) Hoffman rearangement to the appropriate amphetamine (or PEA) ../rhodium /pma.hwe
Meldrum's acids would be better than the malonates but are incredibly expensive.
Another option instead of 4.) may be a Schmidt reaction with NaN3/H2SO4. Though, for unknown reasons it did not work on the ketone 4-(4-Br-2,5-diMeO-phenyl)-butan-2-one to get N-acyl-2C-B with the general conditions as described in Organikum. Maybe I should have try a Beckmann arrangement for that?
“The real drug-problem is that we need more and better drugs.” – J. Ott
(acetaminophanatic)
01-10-04 19:26
No 481714
Ning would like to know why this condensation of a halo-compound with a nitroalkane works in high yield, while the condensation mentioned in Post 475464 (ning: "phencyclidine sans cyclohexanone", Novel Discourse) wouldn't...
Catching a buzz @ the Hive
(Chief Bee)
01-10-04 19:52
No 481719
The presence of a carboxylic ester group beta to the nitro group. Having one electron-withdrawing group on each side of a -CH2- group increases the acidity of those protons a lot, creating a so-called "active methylene group". These are significantly easier to deprotonate/alkylate than simple nitroalkanes.
Read this: http://library.tedankara.k12.tr/carey/ch
The Hive - Clandestine Chemists Without Borders
(Hive Bee)
01-11-04 01:05
No 481776
Ning, in that same thread I used a lot of effort to explain this same question of yours. In Post 475509 (Nicodem: "Ning, the reaction scheme you posted looks so...", Novel Discourse) I said normal nitroalkanes get O-alkylated but in Post 475913 (Nicodem: "Forcing the C-alkylation", Novel Discourse):
"What a chemist can do to improve the C to O alkylation ratio is therefore to make the carboanion more stable, like for example in the ethyl nitroacetate, which can be effectively C-alkylated."
Was I writing all those posts in vain?
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Active Asperger Archivist)
01-11-04 10:38
No 481860
Yes, you were writing them in vain. Most people don't pay attention to the answers provided for them, though they asked in earnest to get such an answer. And, if no one replys, they will certainly bitch about the lack of help here.
I think Rhodium has indeed perfected the manner in which we should respond- short, brief, to-the-point. (as in his reply above) a quick reference to a web page and leave it to them to figure the rest. They will ask more informed questions following their research if they are truly pursuing an answer and not just a "quickie" solution.
Act quickly or not at all.
(acetaminophanatic)
03-17-04 14:06
No 495794
It seems that fine aspect of the issue eluded ning to this point.
Ning appreciates. Thank you~
I'm back.
(Hive Bee)
03-24-04 22:48
No 497201
Lego's mentioned the coverting the benzylbromine to the corresponding phenylacetonitrile via CN addition (SN2 I'm presuming). Is it possible to heat that in a base to form a phenylacetamide then reduce the double bonded oxygen on the alpha carbon using one of reducing techiques posted at the top of this thread?
Or would it be best to reduce the nitrile group with a Zn-Ni coupled catalyst.
Also when working with cyanide, How would one clean up the access cyanide. Swim read that by adding sodium hypochlorite at a ph of 10 to sodium cyanide one may be able to convert it to a cyonate which is less poisoness.
(Hive Bee)
05-12-04 02:14
No 506623
(Rated as: excellent)
Though I had it scheduled to try out this thread's nitroacetate route to PEAs I’m too busy with other stuff and this will have to wait for a while. But meanwhile, maybe some other bee might get interested. In such case the excellent review below might come handy.
The Utility of Nitroacetic Acid and its Esters in Organic Synthesis
M.T. Shipchandler
Synthesis 9 (1979) 666-686.
Abstract: In this review a summary of the syntheses and properties of nitroacetic acid and its esters is given. In addition, their chemical reactivity in the light of their synthetic utility leading to numerous types of nitro compounds, ammo acids, and heterocyclic systems is described.
1. Introduction and Historical Background
2. Methods of Preparation
2.1. Nitroacetic Esters
2.2. Nitroacetic Acid
3. Physical and Spectral Properties
4. Chemical Reactivity
4.1. Nitroacetic Esters
4.2. Nitroacetic Acid
5. Synthetic Utility
5.1. Amino Acids
5.2. Nitro Compounds
5.3. Heterocyclic Compounds
5.4. Carbohydrate Derivatives
6. Recent Developments
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
05-13-04 10:03
No 506900
(Rated as: good read)
Alkylation Of Ethyl Nitroacetate In The Absence Of Solvent.
E. Diez-Barra, A. de la Hoz, A. Moreno
Synthetic Communications, 24(13) (1994) 1817-1821.
Abstract: Alkylation of ethyl nitroacetate by solid-liquid phase transfer catalysis (PTC) in solvent-free conditions has been performed. In regard to other chemical procedures the method provide a simplification of the experimental procedure; however, not in all cases, yield are improved.
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
10-07-04 09:33
No 534834
The method Post 475109 (Lego: "Amphetamines/PEAs w/o benzaldehyde or nitroethane", Novel Discourse) seems to be highly OTC and cheap. Other than manufacturing the methyl nitroacetate the proceedure seems pretty straight forward.
My question is concerning the resulting nitroethane compound. phenylnitroethane compounds are suppose to degrade due to instibility (I haven't had much experience with them).
The nitroethane compound is produced via decarboxylation at 150C according to the example in the post Post 475109 (Lego: "Amphetamines/PEAs w/o benzaldehyde or nitroethane", Novel Discourse).
My question is whether the nitroethane will degrade during this proceedure.