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All 3 posts   Subject: New route to phentermines (+ poss. amphetamines)   Please login to post   Down

 
    Kinetic
(Hive Bee)
11-03-04 20:52
No 539491
      New route to phentermines (+ poss. amphetamines)
(Rated as: excellent)
    

Hellosmile

In my opinion, analogues of the phentermine family - i.e. analogues of the well-known (and lesser-known) psychedelic amphetamines - are worth looking into as novel, legal psychedelics.

However, the usual routes to phentermine and its analogues are crap, leading me to think of a better way. The proposed route below may also work for amphetamines, but I do not yet have any articles detailing the condensation between the necessary propionaldehyde and a benzyl halide. All of the other steps will work equally well without the additional methyl group. The route is almost certain to work for phentermines, and hopefully holds a lot of promise for amphetamine synthesis too. Possibly the best part is that no reducing agents, nor any benzaldehydes, phenylacetones, or nitroalkanes are required. See Lego's recent thread (Post 475109 (Lego: "Amphetamines/PEAs w/o benzaldehyde or nitroethane", Novel Discourse)) for a similar approach, although Lego's proposal requires reducing agents in the final step.

The proposal is detailed for 4-X-2,5-dimethoxyphentermine analogues as far as possible (in order to stir up maximum interest), and I will use the 4-bromo derivative to illustrate my point. One of the beauties of not requiring any reducing agents is that, for example, a nitro group can be introduced to the ring at the beginning of the synthesis, with no fear of reduction to an aromatic amine. So, to start:


1. Bromination of 1,4-dimethoxybenzene
Molecule: ("c1cc(ccc1OC)OC>>c1cc(c(cc1OC)Br)OC")
There are numerous high-yielding ways to make 1-bromo-2,5-dimethoxybenzene. See for example:

Post 269255 (Rhodium: "1,4-MeO-Ph  --AcOH/Br2-->  2,5-MeO-PhBr (90%)", Methods Discourse) (shouldn't this post be uprated?smile)
Post 459979 (demorol: "High-Yielding Halogenations using Halosuccinimides", Chemistry Discourse)
Post 472828 (Nicodem: "2,5-Dimethoxybromobenzene Chloromethylation", Novel Discourse)
Post 514641 (Rhodium: "Aromatic Bromination with NH4Br/H2O2/HOAc", Chemistry Discourse) (as well as Nicodem's excellent post in the same thread)


2. Chloromethylation of 2-bromo-1,4-dimethoxybenzene
Molecule: ("c1(cc(ccc1OC)OC)Br>>c1(cc(c(cc1OC)CCl)OC)Br")
Synthesised according to the procedure developed by Nicodem: Post 472828 (Nicodem: "2,5-Dimethoxybromobenzene Chloromethylation", Novel Discourse)


3. PTC alkylation of isobutyraldehyde with a benzyl halide
Molecule: ("c1(cc(c(cc1OC)CCl)OC)Br.CC(C)C=O>>c1(cc(c(cc1OC)CC(C=O)(C)C)OC)Br")
The procedure below works on ring-unsubstituted benzyl chloride, and should be readily adaptable for a ring-substituted analogue. The yield is 75% for benzyl chloride/isobutyraldehyde:

Catalytic Alkylation of Aldehydes
Hans K. Dietl and Kent C. Brannock
Tetrahedron Letters
, 15, 1273-1275 (1973)



Typical Procedure

In a typical alkylation, a mixture of 140g (3.5 mole) NaOH, 140g water, 200ml benzene, and 14.7g (0.04 mole) tetrabutylammonium iodide was warmed to 70oC. While this mixture was being stirred, a solution of 288g (4.0 mole) isobutyraldehyde and 380g (3.0 mole) benzyl chloride was added dropwise over a 5-hr period. Stirring was continued at 70oC for an addition 2 hr, and subsequent distillation of the organic portion afforded 364g (75%) 2,2-dimethylphenylpropionaldehyde (bp 95oC at 7.2 torr).


4. Synthesis of [substituted] 2,2-dimethylphenylpropionamide
Molecule: ("c1(cc(c(cc1OC)CC(C=O)(C)C)OC)Br>>c1(cc(c(cc1OC)CC(C(=O)N)(C)C)OC)Br")
This is made in one step following a general procedure for the oxidation of aldehydes to amides. There are several ways to do this. The best is probably the JOC article below:

Direct Conversion of Aldehydes to Amides, Tetrazoles, and Triazines in Aqueous Media by One-Pot Tandem Reactions
Jiun-Jie Shie and Jim-Min Fang
Journal of Organic Chemistry
, 68, 1158-1160 (2003)



Representative Procedure for Transformation of Aldehydes into Amides

A solution of appropriate aldehyde (1a-j, 5 mmol) and iodine (5.5 mmol) in ammonia water (30 mL of 28% solution) and THF (5 mL) was stirred at room temperature for 1 h. The dark solution became colorless at the end of reaction. Aqueous H2O2 (3 mL of 35% solution) was then added dropwise. The reaction mixture was stirred for 2-4 h and extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was rinsed with hexane/EtOAc (1:3) to give a pure amide product (3a-j, 81-98% yields).

Alternatives methods for this step are those in Synthesis, 2002, 1057-1060 (solvent-free Beckmann rearrangement of aldehydes to amides using hydroxylamine HCl and ZnO) or Tetrahedron, 58, 10323–10328 (2002) (oxidation of aldehydes to amides using hydroxylamine HCl, methanesulfonyl chloride and wet alumina).


5. Hoffman reaction to give the phentermine
Molecule: ("c1(cc(c(cc1OC)CC(C(=O)N)(C)C)OC)Br>>c1(cc(c(cc1OC)CC(N)(C)C)OC)Br")
The Hoffman reaction was the original route used to make amphetamine; see Post 503731 (Rhodium: "L. Edeleano - The Discovery of Amphetamine", Stimulants). The method is equally applicable to tertiary amides, which would yield phentermine from 2,2-dimethylphenylpropionamide. The reaction conditions are a little more vigorous however, as the intermediate tertiary isocyanate is more stable to hydrolysis than its secondary cousin.

The classic Hoffman reaction uses either an alkali metal hypohalite directly, or an alkali metal hydroxide with bromine, to generate an alkali metal hypobromite in-situ. The latter is exemplified by the following synthesis of 1-methylcyclohexylamine, taken from Journal of the American Chemical Society, 75, 369-373 (1953):

Method B. 1-Methylcyclohexylamine

The well known Hofmann reaction19 was used to convert the tertiary carboxamides to the desired amines given in Table I. The following example is illustrative of the method. A solution of 85 g. (0.52 mole) of bromine in 1450 cc. of 20 % potassium hydroxide solution was stirred and cooled in an ice-bath while 74 g. (0.52 mole) of 1-methylcyclohexanecarboxamide was added as a fine powder. After stirring for an additional one-half hour, the resulting isocyanate was extracted from the alkaline mixture with ether. The ether extract was added dropwise while stirring to 200 cc. of boiling concentrated hydrochloric acid. After the liberation of carbon dioxide had ceased, the hydrochloric acid solution was concentrated in vacuo. The crystalline residue was recrystallized from absolute ethanol-ether; m.p. 285o with decomposition, yield 62 g. (80%). The free base was obtained in the usual manner by treating an aqueous solution of the hydrochloride with alkali, extracting with ether and distilling.

There is also a more modern (by a century) version of the Hoffman reaction which proceeds under acidic conditions. [Hydroxy(tosyloxy)iodo]benzene is known to do this (and this reagent also oxidises alpha-methlystyrenes to phenylacetones) but iodosobenzene can also be used with formic acid, making the synthesis more bee-friendly. Yields range from 70-90% in the following example:

Conversion of Amides to Amines using Iodosobenzene
Arakali S. Radhakrishna, C. Gundu Rao, Rakesh Kumar Varma, Bajrang Bali Singh, Surendra P. Bhatnagar
Synthesis
, 1983, 538



Amines 3 from Amides 2 using Iodosobenzene (1); General Procedure:

To a stirred suspension of iodosobenzene (1; 2.4 g, 11 mmol) in acetonitrile/water (15 ml + 5 ml), formic acid (85%; 2 g) is added with stirring. Within minutes the reaction mixture becomes homogenous. To this solution is added the amide 2 (10 mmol) in one lot and stirring is continued at room temperature for 15 h. The mixture is diluted with water (25 ml), acidified with concentrated hydrochloric acid (5 ml) and iodobenzene extracted with ether (2 x 10 ml). The aqueous layer is separated and evaporated to give the amine hydrochloride which is crystallised from an appropriate solvent.

Questions, comments and suggestions are very welcome.
 
 
 
 
    Nicodem
(Hive Bee)
11-04-04 18:45
No 539683
User Picture 
      That’s a good combination of ideas     

I just love the idea of going trough the aldehyde, thus avoiding the tedious alkylation of isobutanoic or propionic acid esters which would require not at all kitchen friendly conditions like -78°C and bases like LDA or NaH. This and the addition of the elegant and, at least for me, completely unknown method for the direct transformation of the aldehydes to amides. Congratulations, combining this two was a stroke of genius.wink

Comments on the proposal:
I realize that the benzylchloride substrate was chosen just the sake of representation of the idea, but still I should say something about this specific example.
There is a potential problem that might result from the o-MeO group. It could hinder the access to the nucleophyle. Lower yields than the ones reported for the plain benzylchloride might be expected.
It is known that the o-MeO reduces the yield in certain reactions involving benzylchlorides. For example, the classical Sommelet reaction on such substrates gives low yields of the aldehyde in addition to the benzylamine side product which is otherwise practically not present.
Unfortunately the Tetrahedron Letters paper only reports the results of the plain benzylchloride, while the negative results for the only somewhat stericaly hindered halide tested, the isopropyl bromide, quite probably arise from it not being activated and maybe because of a concurring elimination side reaction (the also non-activated MeI at least gave a 15% yield, but with this they could also work at a higher temperature since no elimination can occur before all isobutyraldehyde self condense).
Anyway I would still expect a useful, though not fully satisfying, yield from the reaction with 4-Br-2,5-diMeO-benzylchloride.
I’m also convinced that this method would not work for the condensation between the propionaldehyde and a benzyl halide (for amphetamines). Not only because, if it would, the authors would have reported it, but also because propionaldehyde is much more prone to self condensation than isobutyraldehyde is. After all, the authors themselves state that the better results obtained for the alkylation of 2-ethylhexanal are due to its greater stability toward sodium hydroxide. But at least for getting to the amphetamines trough the Hoffman reaction you can use the alkylation of 2-methyl-malonic esters (Post 481578 (Nicodem: "Another similar route from benzylhalogenides,...", Novel Discourse)) or the proved method in https://www.rhodium.ws/chemistry/amph.acetoacetate.html.

I truly hope somebee will try this out and report on the psychoactivity of the substituted phentermines according to the psychedelic patterns.cool

“The real drug-problem is that we need more and better drugs.” – J. Ott
 
 
 
 
    Kinetic
(Hive Bee)
11-12-04 22:34
No 541287
      Alkylation as a route to chiral amphetamines
(Rated as: excellent)
    

Thanks for your comments Nicodem. I have taken ther past few days to arm myself with several more interesting references.wink

Virtually all of the final products I am interested in will have a methoxy group in the 2-position, so I hope this doesn't interfere and lower the yield during the alkylation. Hopefully it is not steric interactions which cause the low yield of aldehyde in the example of the Sommelet reaction you gave; if I have interpreted it correctly, the presence of the benzylamine indicates the substituted benzyl chloride has at least been able to alkylate the bulky hexamine molecule before being hydrolysed. Hopefully it is some other force at play in this case.

To back this up, Chem. Ber, 127, 2277-2283 (1994) details of the alkylation of the sterically similar (to isobutyraldehyde) ethyl isobutyrate with 2-methoxybenzyl bromide, proceeding in 64% yield. This was a more 'traditional' alkylation, using a lithium enolate (formed from LDA and the ester in THF at -78oC) which was reacted with a single equivalent of the benzyl bromide. Since the yields reported for alkylations of esters with unsubstituted benzyl halides under these conditions are generally in this region anyway, I am hoping that the yield in the alkylation with isobutyraldehyde is also relatively independent of the 2-substituent.

With regards the alkylation of propionaldehyde, I agree. If something so simple isn't reported in the literature, there is generally a reason. However it is possible to alkylate derivatives of propionaldehyde with benzyl halides. The one paper I came across is a very interesting one as it is an enantioselective synthesis of the aldehyde, giving a 62% yield with an ee of 82% for our substrate. The subsequent transformation of the aldehyde to the amide as in my previous post should proceed with retention of stereochemistry (see the note in the paper below), and the Hoffman reaction - at least the modified version - to the amphetamine definitely will. Here is the alkylation paper:


Enantioselective Alkylation of Aldehydes Via Metalated Chiral Hydrazones
Dieter Enders* and Herbert Eichenauer
Tetrahedron Letters
, 2, 191-194 (1977)



(R)-2-Methyloctanal 5e
Compound 6, (2.6g, 20 mmol) is treated dropwise with n-octanal (3.12ml, 20mmol) with stirring at 0°. After 2 hr the crude product is dissolved in CH2Cl2 and the resulting solution dried over sodium sulfate, concentrated in a rotary evaporator, and finally purified by column chromatography (silicagel, n-pentane/ether 3:1). 2, R1= n-C6H13 is obtained in 96% yield (4.6g) as a colorless oil, [alpha-]D22= -l03° (c=1.8, benzene). 2 (2.4g, 10mmol) is metalated according to the method of Normant et al. (metalation time 10h) , cooled to -95° and treated with a solution of methyliodide (0.68ml, 11mmol) in 15 ml THF. The mixture is stirred for a further 3 hr and allowed to warm to room temperature. After hydrolysis, work up with ether yields 4, R1= n-C6H13, R2 = CH3, 2.3g (91%). The crude product is treated with excess methyliodide and stirred at 60° for 5 hr. The resulting salt is hydrolysed in a two-phase system (3N HCl, n-pentane) by rapid stirring for 30 min. 5e is purified by molecular distillation over glass wool (oil bath temperature 100°/3 torr).


The Hoffman reaction has been recently used on chiral amides to product chiral amines, hence beginning with a single enantiomer of  2-methyl-3-phenylpropionamide will give enantiomerically pure (R)- or (S)- amphetamine. How can I be so sure? See the article below.wink


N-Acyl ‘Quat’ pyrrolidinone auxiliary as a chiral amide equivalent via direct aminolysis
Stephen G. Davies * and Darren J. Dixon
Journal of the Chemical Society, Perkin Transactions 1
, 2002, 1869–1876

Abstract
A novel route to chiral amides through the efficient, non-racemising, cleavage of N-acyl side chains from a ‘Quat’ chiral auxiliary using N-centred nucleophiles is described. The synthetic utility of the procedure is then highlighted by the preparation of a range of succinamide and succinimide derivatives and through the synthesis of the natural product (S)-(+)-amphetamine via a stereospecific Hoffman type degradation using a hypervalent iodine reagent.



Preparation of (S)-(+)-amphetamine HCl (S)-6
To a stirred solution of amide (S)-4 (0.050 g, 0.307 mmol) in acetonitrile–distilled water (1 : 1, 2 ml) at room temperature was added [bis(trifluoroacetoxy)iodo]benzene (0.198 g, 0.460 mmol) in one portion. The reaction mixture was stirred at room temperature for 5 hours and was then quenched by the addition of aqueous hydrochloric acid (1–M, 10 ml). The aqueous layer was extracted with diethyl ether (2 x 20 ml) and concentrated in vacuo to yield a white solid. Recrystallisation of this material from ethanol–diethyl ether afforded the title compound (S)-6 as white needles (0.048 g, 91%)


It should be possible to prepare butanamines via alkylation of derivatives of butyraldehyde. There is also another very interesting avenue to explore: the alkylation of nitriles, followed by controlled hydrolysis to the amide, which can of course be subjected to the Hoffman reaction to give the amine. At first glance, it would seem that propionitrile can be alkylated, which will overcome the problems with the alkylation of propionaldehyde. But the credit for the idea of using nitriles should go to Nicodem.
 
 

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