Author Topic: Modified ketamine method  (Read 6171 times)

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Modified ketamine method
« on: May 07, 2004, 07:05:00 AM »
In zealot's fine ketamine synthesis (

), as well as the standard route (they are much the same)(


cyclopentyl grignard is reacted with o-chlorobenzonitrile to yield o-chlorophenyl cyclopentyl ketone, which is then brominated, and hydrolyzed to give (1-hydroxy-cyclopentyl)-(o-chlorophenyl)-N-methylketimine. This is rearranged by heat to give ketamine.

The key intermediate is this, or something similar:


very tasty ("Clc1ccccc1C(=O)C2(O)CCCC2")

It is reacted with methyl or other amine to give the ketimine which will rearrange to the desired cyclohexylamine.

Only problem is, the standard synthesis is very long and annoying. It's no surprise that few clandestine labs make ketamine. Yuck!

I propose the following modification, to shorten the path drastically:

o-chlorobenzyl grignard is reacted with cyclopentanone:


grignard ("Clc1ccccc1CCl.O=C2CCCC2>>Clc1ccccc1CC2(O)CCCC2")

o-chlorobenzyl cyclopentanol is oxidized with KMnO4 at the benzylic position to yield o-chlorophenyl hydroxycyclopentyl ketone, which can bee used as usual in the ketamine ring expansion.


oxidize,KMnO4 ("Clc1ccccc1CC2(O)CCCC2>>Clc1ccccc1C(=O)C2(O)CCCC2")

where's the REFS? THE REFS!

Right, the refs.

Well, the grignard is easy. I almost hesitate to include the refs, but since I found some, here is the best:

cyclopentanone + benzyl bromide -- JOC 2001, 8573

 75% yield for a sequence of grignard addition, dehydration, and ozonolysis. What was the yield of grignard then? HIGH. General procedure:
"Under an atmosphere of N2, an ethereal solution (20 mL) of Grignard reagent was prepared from bromobenzene (6.0 g, 38 mmol) and Mg (960 mg, 40 mmol) by the activation of I2 (small amount). A solution of cyclopentanone (2.5 g, 30 mmol) in ether (10 mL) was added dropwise at room temperature. The mixture was stirred for 2 h and then poured into an ice-cold 1 N HCl solution (60 mL). The mixture was extracted with ether times, the extracts pooled, dried over Na2SO4, and concentrated to give a crude addition product."
<< after dehydration w/ TsOH, yield 93%. Final yield 82%. This suggests yield for benzyl chloride product on the order of > 85%. >>

Bee careful on the workup of the crude product, as it would very much like to dehydrate into an alkene conjugated with the phenyl ring. Don't purify it, because the permanganate oxidation will probably reoxidize this to the desired alpha-hydroxy ketone. No need to throw away yield percentage!

And that brings us to the real meat of the problem--the permanganate benzylic methylene oxidation. Ning has worked hard to find many useful papers related to this.

JOC 1997, 8767 : Heterogeneous Permanganate Oxidations. 7. The Oxidation of Aliphatic Side Chains

Equal weights of potassium permanganate and copper sulfate pentahydrate were ground together in a mortar. The resulting fine, highly colored product was then used as a heterogeneous oxidant in methylene chloride solutions.

                                       time(h)  yield
ethyl benzene   --> acetophenone           70    95%
propyl benzene  --> ethyl phenyl ketone    70    90%
butyl benzene   --> propyl phenyl ketone   72    88%
indane          --> indanone               72    78%
cumene          --> 2-phenyl 2-propanol   (70?)  78%
sec-butylbenzene--> 2-phenyl 2-butanol    (140?) 79%

Oxidation of Isochroman:

0.188 g / 1.4 mmol dissolved in 20 mL DCM with 3.2 g oxidant were placed in 50 mL RBF and refluxed gently. After 72 h, the product was filtered through a Celite pad and the residue washed successively with DCM (3 x 20 mL) and ether (ditto). Evaporation gave the lactone, 2-chromanone (0.198 g, 1.35 mmol, 96%).

A good proof of concept, BUT, too big excess of permanganate and TOO SLOW! This is solved by PTC, as we shall see in the next few papers.
Note the oxidation of cumene to a tertiary alcohol. This is what I'm talking about!

Synthetic Communications 2003, 1057 : Ion exchange catalysis in oxidation of organic compounds with KMnO4

Oxidation of Indan with KMnO4/IER:

Indan (0.118 g, 1 mmol) was dissolved in 30 mL DCM and placed in a RBF with mag stirring. Finely ground KMnO4 (1 g) and Ion Exchange Resin (1 g) were added and the mixture stirred at reflux, monitored by TLC. After 7 h, reaction was complete. Product was filtered through sintered glass and the residue washed with 20 mL DCM and evaporated to give 0.93 mmol, 93% of indanone.

                                       time(h)  yield
ethyl benzene   --> acetophenone           5.5   91%
propyl benzene  --> ethyl phenyl ketone    5.8   93%
butyl benzene   --> propyl phenyl ketone   5.8   92%
tetralin        --> tetralone              7     95%
indane          --> indanone               7     93%
toluene         --> benzoic acid           3     90%

They also oxidize a lot of other stuff, i.e. alcohols, sulfides, thiols, etc. Note the improved reaction time. Still not on a good scale yet, though.

J. Chem. Research (Synopses) 2000, 38 : Cation exchange resin supported oxidation of alkylbenzenes and olefins using potassium permanganate

Typical procedure for oxidation of alkylbenzenes:
KMnO4 (0.948 g, 6 mmol) is added to a suspension of Tulsion T-40 resin (2 g), t-butyl alcohol (4 ml) <<note--it's oxidation proof. Try acetone or MEK as well>>, water (1 ml), tetralin (246 mg, 2 mmol) in DCM (20 ml) in lots during 10 min time. The reaction mixture was stirred at room temp for 4 h, filtered and dried over anhydrous Na2SO4. After removing the solvent, the product obtained is purified by column chromatography to get a-tetralone (263 mg, 90%)

                                        time(h)  yield
ethyl benzene   --> acetophenone            4.5   86%
tetralin        --> tetralone               4     90%
isobutylbenzene --> Isopropyl phenyl ketone 5     88%
cumene          --> 2-phenyl 2-propanol     4     82%

Note that in this paper, they are only using a 3-times excess of KMnO4. Still, the scale isn't BIG enough!! ::)

Synthesis 1989, 293 : A convenient oxidation of benzylic methyl, methylene, and methine groups with potassium permanganate/triethylamine reagent

KMnO4 (1.58 g, 5 mmol) and Et3N (506 mg, 5 mmol) are first mixed in a RBF, followed by addition of water (1 ml) and CHCl3 (20 ml) or 1,2-dichloropropane under magnetic stirring. The permanganate color fades and the mixture turns into a brick color with a gentle evolution of heat within 3 minutes. After addition of the substrate (5 mmol), 3 mL of 6 M H2SO4 is added dropwise. Oxidation proceeds immediately at 20 C as acid is introduced, and is completed after an additional stirring for 30 to 90 minutes at RT, as indicated by TLC. The mixture remains homogeneous during the reaction. 30 ml CHCl3 is then added to the mixture and the coloidal MnO2 is filtered with the aid of silica gel (5 g) and CaCl2 (1 g, also acts as drying agent). This operation also provides considerable purification, and concentration of the filtrate on a rotary evaporator usually leads to pure product.

For tertiary benzylic alcohols like triphenylmethane and 2-phenylpropane, a 2:1 ratio of KMnO4 to substrate is used because they are less reactive.

                                        time(h)  yield
ethyl benzene   --> acetophenone                  58%
tetralin        --> tetralone               4     84%
triphenylmethane--> triphenylmethanol       5     46%
cumene          --> 2-phenyl 2-propanol     4     61%

Yield not so good, but it shows that alternate methods are possible.
Their method works better for diaryl methylene groups.

Now, for some real fun--complex functionalized compounds!
Tetrahedron 2003, 1309 : Page 1314

Preparation of 8-acetylamino-4-(2,2-dimethyl-1,1-diphenyl-silapropoxy)-6-fluoro-5-methyl-1-one-2,3,4-tetrahydronaphthalene: <<where do I get the idea they used autonom to name this?>>


damn man, I can't read that! ("c1ccccc1[Si](c2ccccc2)(C(C)(C)C)OC3CCCc4c3c(C)c(F)cc4NC(=O)C>>c1ccccc1[Si](c2ccccc2)(C(C)(C)C)OC3CCC(=O)c4c3c(C)c(F)cc4NC(=O)C")

To a solution of (the former) (0.13 g, 0.27 mmol) in 6.4 mL acetone and 0.64 mL 15% aq. MgSO4 was added 210 mg (1.4 mmol) KMnO4 in portions at 0 C. After stirring for 2 h at RT, the reaction mixture was diluted with water and extracted with chloroform. The organic phase was washed with saturated NaHCO3 and sat. NaCl, dried with Na2SO4 and evaporated. Yield 93 mg, 0.2 mmol, 74%.

Tetrahedron Asymmetry 2001, 2283 : page 2285

KMnO4 oxidation of 1-tetralin acetate:

To a cooled soln. of 1-acetoxytetralin (0.67 g, 3.54 mmol) in 15 ml acetone was added 2.08 g (8.43 mmol) MgSO4.7H2O and 5 ml water. To this mixture, 2.88 g (18.3 mmol) KMnO4 was added in small portions over 1 hour and stirred further for 4 h at RT. The solid was filtered off and the filtrate treated with satd. soln. of potassium metabisulfate. The resulting mixture was again filtered and extracted thrice with 25 ml DCM. The pooled extracts were washed with water, brine, and dried over Na2SO4. Solvent was removed and product chromatographed. Yield 0.46 g, 64%.

KMnO4 oxidation of 1-acetoxyindane:

Procedure was the same as above. Compound was prepared from acetoxyindane in 80% yield.

Finally, an oldie but goodie, for those who like the traditional methods. They use nitric acid on bentonite clay.

Synthetic communications 2002, 3565 : Natural bentonite clay / Dilute HNO3 (40%) -- A mild, efficient, and reuseable catalyst/reagent system for selective mono nitration and benzylic oxidations

General procedure for oxidation:
A dry 100 ml 2-necked RBF is fitted with a dean-stark trap and charged with 5.3 g (0.05 mol) ethylbenzene and 5 g bentonite clay. To this, 50 mL of hexane and 20 mL 40% HNO3 are added and refluxed for 5 h. At this time, water level in dean-stark trap remains constant and TLC shows completion. After filtering, solvent removal, and chromatography, there is collected acetophenone 5.3 g, 89%.

                                        time(h)  yield
ethyl benzene   --> acetophenone            5     89%
diphenylmethane --> diphenylmethanol        5     81%
isobutylbenzene --> Isopropyl phenyl ketone 5     41% (??)

Unfortunately, the reaction is annoying and as the paper title indicates, it is probably that aromatic nitration is a competitive reaction. Nonetheless, for those who absolutely, positively can't get permanganate, it's nice to know that there may be alternatives.

Tired of the blabber yet?? It just goes on and on!!

What makes this pathway theoretically better than the current one:

-- In zealot's synthesis, cyclopentanone is made from adipic acid. This has to be made into cyclopentyl bromide through several annoying steps. This synthesis uses the cyclopentanone directly, skipping the extra work.

-- This synth uses a benzyl chloride rather than a benzonitrile. Benzyl chlorides are easier to make than benzonitriles, by chloromethylation from functionalized benzenes, free radical chlorination of toluenes, or reaction of benzyl alcohols with hydrochloric acid. This also saves some work, especially if you decide to make deschloroketamine. Then it's from toluene or benzyl alcohol, both rather OTC.

-- This synth avoids the use of bromine or bromides. This makes it more OTC and cheaper. No NaBr or HBr, no NBS or Br2.

-- Benzyl chloride grignard is very easy to start. For what it's worth.

So, the rundown for a hypothetical "OTC" K (analog) synthesis:

Zealot method:

1. toluene + KMnO4 --> benzoic acid
2. benzoic acid + urea + sulfamic acid --> benzonitrile
3. adipic acid + Ca(OH)2 --> cyclopentanone
4. aluminum + isopropanol + CCl4 + HgSO4 --> aluminum isopropoxide
5. aluminum isopropoxide + cyclopentanone --> cyclopentanol
6. cyclopentanol + HBr --> cyclopentyl bromide
7. cyclopentyl bromide + Mg + benzonitrile --> phenylcyclopentyl ketone
8. phenyl cyclopentyl ketone + Br2 + dioxane --> phenylbromocyclopentyl ketone
9. phenyl bromocyclopentyl ketone + methylamine --> phenyl hydroxycyclopentyl N-methylketimine
10. the above + heat --> deschloro ketamine!!!

This method:

1. toluene + TCCA + PTC --> benzyl chloride
2. adipic acid + Ca(OH)2 --> cyclopentanone
3. benzyl chloride + Mg + cyclopentanone --> benzylcyclopentyl ketone
4. benzylcyclopentyl ketone + KMnO4 + PTC --> phenyl hydroxycylopentyl ketone
5. phenyl hydroxycyclopentyl ketone + methylamine --> phenyl hydroxycyclopentyl N-methylketimine
6. the above + heat --> deschloro ketamine!!!



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Another benzylic oxidation paper
« Reply #1 on: May 09, 2004, 05:09:00 PM »

" Oxidative Synthesis of Benzoylpteridines from Benzylpteridines by Potassium Permanganate", Bulletin of the Korean Chemical Society
Volume 22, Number 2(2001)


Yet another. This one uses Fe(II)<-->Fe(III) catalytic oxidation method--i.e. H2O2 + FeCl2 or something.

I'm reading the entire journal! Don't you love free full-text online journals?