--------------------------------------------------------------------------------
 Discussions on the preparation of piperonal from the pepper alkaloid piperine
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Area: alt.drugs.chemistry
Subj: piperonal
From: flipside@ix.netcom.com(Al Kowalewski )

Hey anyone,
I've always wondered about using black pepper as a source for
piperonyl, especially after reading about an extraction process
in "Natural Products: A Lab Guide" by Ralph Ikan. This CAN be
done but there are a few details that some of you geniuses out
there could figure out for us.
Anyway, here's the idea....

Black pepper (which is really really easy to get large quantities
of!!!) contains piperine in a fairly good amount (like 3 to 5%)
and is really easily extracted with ethanol...
                                                      ___
                                O   ___              /   \
                               / \ / _ \            N     >      
Black pepper ---------------> <   < (_) >--\//\//\ / \___/  
                   EtOH        \ / \___/         ||      
                                O                 O

1. Reflux the black pepper in ethanol, filter and concentrate the
filtrate by evaporation. Add the extract to 10% KOH in ethanol.
Heat and add water dropwise. A volumous yellow precipitate forms.
Add water until no more appears. It will crystalize upon standing
overnight. Collect the solid and recrystalize from acetone. This
is piperine.
                          ___ 
   O   ___               /   \ 
  / \ / _ \             N     >       
 <   < (_) >--\\//\//\ / \___/    -------------->   
  \ / \___/          ||           EtOH+KOA+heat
   O                  O
                               ___ 
   O   ___                    /   \ 
  / \ / _ \            OH    N     >       
 <   < (_) >--\//\//\ /   +   \___/     
  \ / \___/         ||         
   O                 O

2. Reflux piperine in KOH+ethanol under reduced pressure until
dryness. Suspend the residue in water, heat and then acidify with
HCl. Collect the yellow precipitate of piperic acid.
                                
   O   ___                                O   ___
  / \ / _ \            OH                / \ / _ \      
 <   < (_) >--\//\//\ /   +  KMnO4 ---> <   < (_) >--\  /
  \ / \___/         ||                   \ / \___/    \/
   O                 O                    O           ||
                                                      O
                  
3. Piperic acid is oxidised with potassium permanganate (or some
other oxidizer) to yeild piperonyl....

Actually you end up with piperonyl, piperonylic acid and/or
piperonyl acetone in varying quantities.

Here's the question - how do you make the last part work to give
a good yeild of piperonyl (or your choice of any)?

Any help is appreciated (help with the ASCII molecules is
appreciated as well!)

-- AL      

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(1) Place 30g of finely ground black pepper in a porous thimble 
in the central chamber of a soxhlet extractor and 175ml of 95% 
ethanol in a RB flask. Gently heat solvent under reflux for
6 hours. Concentrate the solution to a volume of 20-30ml on a 
rotary evaporator and add 30ml of warm 2M ethanolic potassium 
hydroxide (this is ESSENTIAL to keep all the acidic components in 
solution). After shaking the warm mixture well, filter the solution 
and remove any insoluble materials (quite a bit). While keeping the 
solution warm over a water bath, and water until no more yellow 
solid forms. Allow the resulting solution to stand overnight and 
then isolate yellow precipitate that has formed by filtration. 
Recrystalise the crude product in hot 3:2 acteone/hexane, cooling 
in ice bath if necessary to promote recyrstallisation. The resulting 
product (Piperine) is in the form of spectacular yellow needles, a 
yield of around 2g (in my case) was obtained.

(2) Hydrolysis of Piperine to Piperic Acid: (These intructions are 
in the small scale, obviously they can be increased) Heat mixture of 
0.1g piperine and 10ml of 2M ethanolic potassium hydroxide under 
reflux for 1.5h. Evaporate the ethanolic solution to dryness under 
vacuum. Suspen the solid potassium piperate that remains in the flask 
in about 5ml of hot water and carefully acidify the suspension with 
6M HCL. Collect the precipitate, wash with cold water, recyrystalise 
from COLD ethanol. The mp of the product should be around 206C (a 
little less than the literature values due to the slight Chavacine 
impurification (Chavacine is the Z,Z isomer of piperic acid (E,E))
                  
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Cherrie Baby - posted at the Hive 09-12-98 

I'm not too keen on your scheme. (explanation below)

Piperonal can be obtained from black pepper via piperine which is present as 
5-7% of pepper. Pepper is quite cheap and easy to get hold of in bulk. (£4/Kg).

Piperine --> piperic acid + piperidine (Fittig and Mielch, Ann., 152 (1869) 25)
by hydrolysis of piperine with alcoholic KOH

piperic acid + KMnO4 --> piperonal (Fittig and Mielch, Ann., 152 (1869) 25)

I imagine the oxidation looks like this: (Please check equations - someone)

piperic acid + 4(O) --> piperonal + CH2.(CHO)2 + OHC.CO2H

Several other oxidations are possible using: HNO3, H2O2/V2O5, O3, gamma-rays, 
CrO3/H3PO4, Na2Cr2O7/Mn4+.

Next I'd like to try this novel route:

Piperonal + yeast --> MD-phenyl-CH(OH).CO.Me

Neocelsis gives us Journal of Fermentation and Bioengineering 84, 487-492 (1997)
Pure and Applied Chemistry 1997, vol 69, ppgs 2371-2385 
But says that "Sadly when ring substituted benzaldehydes are used the yield 
falls off badly" Sadly I'll have to see how badly.

MD-phenyl-CH(OH).CO.Me --> 1-(MD-phenyl)-2-methyl-glycol
MD-phenyl-methyl-glycol + acid --> isosafrole

This is all quite novel, inefficient, crazy and perfectly OTC. I feel that I 
should get something ready for the day when sassafras oil becomes a totally 
controlled substance.

But remember - you speed freaks out there - this is also more applicable to meth.

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Cherrie Baby:
      
Jerry March - (pages 1181-82) on oxidative cleavage of double bonds:

With ordinary solutions of permanganate or dichromate the yields are generally 
low and the reaction is seldom a useful synthetic method; but high yields can be 
obtained by oxidising with KMnO4 dissolved in benzene containing the crown ether
dicyclohexano-18-crown [J. Am. Chem. Soc. 94, 4024 (1972); J. Org. Chem. 43, 
1532 (1978)

With certain reagents the oxidation can be stopped at the aldehyde stage, and 
in these cases the products are the same as the ozonolysis procedure. 
Among these reagents are:

chromyl trichloroacetate: Liebigs Ann. Chem. 659, 20 (1962)
t-butyl iodoxybenzene: Tetr. Lett. 26, 4955 (1985)
KMnO4 in THF-H2O: J. Org. Chem. 51, 3213 (1986)
NaIO4-OsO4: J. Org. Chem. 21, 478 (1956)

That KMnO4 in THF looks very enticing - I'll mail the procedure ASAP.
  
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Cherrie Baby:
      
The following abstract appears to contain a mistake - it talks about making 
MDP-acetyl carbinol by fermenting vanillin with yeast. I thought I'd flashed 
back to acidtopia when I first saw it - funky yeast - yeh!! They probably meant 
via fermentation of piperonal. US pat. 3338796 will, hopefully, have more info. 
on MDP-acetyl carbinol.

MDP-acetyl carbinol is easily reduced to b-Me-MDP-glycol, from which MDP2P can 
be obtained by our dear friend the Pinacol rearrangement. The total process is 
untried so yields are as yet unknown. But everything is very OTC.

Piperonal can, itself, be obtained by oxidation of piperic acid (from pepper) 
with KMnO4 in THF or with PTC. [see the references above, in my previous post]. 
The amount of KMnO4 used must be strickly limited so as not to over-oxidise to 
the MD-benzoic acid.

I hope to get this patent next Monday.

Chemical Abstracts Vol. 67, 1967, page 8432, 89797u
Converting veratraldehyde to L(-)3,4-dimethoxyphenylacetyl carbinol. John W. 
Rothrock (to Merck & Co. Inc.). U.S. 3,338,796 (Cl. 195-28), Aug. 29, 1967, 
Appl. Aug. 19, 1964, and Oct. 13, 1966; 2 pp.

L(-)3,4-Dimethoxyphenylacetyl carbinol (3,4-(MeO)2C6H3CH(OH)Ac) is produced by 
contacting veratraldehyde with a growing acyloin-producing culture of Aerobacter 
aerogenes ATCC 211; the product is isolated by extn. and crystn. Thus, medium 
contg. com. yeast ext. 20, dextrose 20, MgSO4 7 H2O 0.5, KH2PO4 0.2, and Na2HPO4 
0.2 g./1., with pH adjusted to 7, is inoculated with a strain of Saccharomyces 
cerevisiae; the medium is aerated and agitated at 28° for 48 hrs. The agitation 
and aeration are stopped. Vanillin is added to give a concn. of 4 g./1. The 
agitation and aeration are resumed and continued for 7 hrs. to produce 
L-3,4-(methylenedioxy)phenylacetyl carbinol. The fermentation broth is 
sterilized and filtered to remove the cells. The filtrate is satd. with NaCl and 
extd. 4 times with 1/3 vol. of EtOAc. A crude product is obtained after evapg. 
the EtOAc. A by-product of the fermentation process is removed by crystn. from 
an EtOAc-petroleum ether soln. of the crude product. The mother liquor contains 
the desired product, the solvents are removed by evapn. and the residual oil is 
subjected to partition column chromatog. using diatomaceous earth and a solvent 
mixt. of C6H6-EtOAc-MeOH-H2O (9:1:5:5). The fractions eluted are vanillyl alc., 
vanillin, and a mixt. of vanillic acid and L-3-methoxy-4-hydroxyphenylacetyl 
carbinol. The last fraction is fractionally crystd. from a mixt. of 
EtOAc-petroleum ether to remove vanillic acid. The mother liquor contg. the 
product is further purified by extn. by aq. Na2SO3 to ext. acetyl carbinol as a 
bisulfite. The bisulfite addn. product is decompd. by addn. of an excess of an 
aq. soln. of Na2CO3. The product is extd. with EtOAc. The ext. is evapd. to a 
small vol. to cryst. L-3-methoxy-4-hydroxyphenylacetyl carbinol; m.p. 69-73°, 
[a]D23 = 211° (c 1.02%, acetone). L-3,4(Methylenedioxy)phenylacetyl carbinol, 
m.p. 44-6°, [a]D25 = 228° (c 1.2% EtOAc), and L-3,4-dimethoxyphenylacetyl
carbinol were also produced by the method. S. P. Marino

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Cherrie Baby:

Last post was a little off topic but the same error occured in the patent - as 
well. So that's a grand total of 1 author, 2 patent examiners and 1 Chemical
Abstracts transcriber who failed to notice the obvious error - 1 mentioned 
previously!!

Isolation of Piperine from Black Pepper - J. Chem. Ed. 70(7), 598-9 (1993)

Hydrolysis to Piperic acid (might not be needed (at Rhodium's)

Oxidative cleaveage to Piperonal with cetyltrimethylammonium permanganage - 
see Synthesis 1984, p 431-3. They also give details for making CtMe3N MnO4 
from CtMe3NBr - but I can't see why CtMe3NCl shouldn't work just as well 
(CtMe3NCl is ubiquitous in loads of OTC skin & Hair products) - I intend to 
try this first with fabric conditioner - it's cheaper but is less hydrophilic 
(so might not work!).

Also J. Chem Research - Synopses 1986, p 458-9 for "Cetyltrimethylammonium 
Permanganate: a Useful Reagent for the Selective Oxidative Cleaveage of 
Aryl-substituted Olefins"

R4N+ MnO4- is one reagent to use, expected yield of piperonal ~74% with this:

The benzylic alkene of piperic acid should cleave to aldehydes (either side) 
and other, purely aliphatic alkene group will give a diol.

Alternatives are to use (2) aq. KMnO4 with substrate in THF - it might work 
- see J. Org. Chem. 51, p 3213 (1986). Or (3) PTCs, which include: Crown 
ethers (too expensive), TDA-1 - see Synthetic Commumications 17 p 647-55 
(1987), Dimethyl polyethylene glycol - see J. Org. Chem. 43, p 1532, (1978).

General Procedure for the Oxidative Cleavage with CTAP

To a stirred solution of the alkene substrate (1 mmol) in DCM (7 mL) was 
added a solution of CTAP (1 mmol) in DCM (6 mL) at 25°C. After 2-6 h, 
diethyl ether (50 mL) was added and the reaction mixture was filtered 
through a pad of Celite and anhydrous MgSO4. The filtrate was concentrated 
in vacuo and the crude product was purified by chromatography on silica 
gel to afford the pure carbonyl product. [From: J. Chem. Res. (S), 1986, 459]

Note (mine): CTAP: cetyltrimethylammonium permanganage.

Why do they add diethyl ether and not more DCM? Surely better to stick with 
just one solvent so that it can be recycled?

Cetyltrimethylammonium Permanganate, CTAP

To a stirred solution of potassium permanganate (3.168 g, 20 mmol) in water 
(100 mL) at 20°C is added, dropwise over 20 min, a solution of CTAB - 
Cetyltrimethylammonium Bromide (8.02 g, 22 mmol) in water (100 mL). A fine 
violet precipitate forms immediately. Stirring is continued for 30 min, the 
precipitated product is isolated by suction, washed thoroughly with water, 
and dried in a dessicator over phosphorus pentoxide in vacuo for 3 h at room 
temperature to give the salt as a fluffy violet solid; yield: 6.5 g (80%). 
The reagent is stored in a brown bottle in the refrigerator. [From Synthesis 
1984, p 431]

Notes: a suitable alternative to CTAB is CTAC aka Cetrimide or Cetrimonium 
Chloride - found in hair conditioners. [A small cosmetics company would have 
no difficulty getting hold of mucho supplies of this in mega quantities]

An alternative dessicant to the P2O5 is KOH or NaOH? Why not? Dessication is 
essential and these quaternary ammonium compound are very hygroscopic.

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Piperine to Piperonal Procedure, by The Cook

Piperine is extracted from B. Pepper with an organic solvent. Duh.
Anhydrous alcohols are fine, ether is much cleaner. Solvent is evap'd to
leave yellow crystals.

Hydrolize with NaOH in Alcohol. (MeOH/EtOH both verified)

Oxidize with Potassium Permanganate, to get a flask full of chopped-up
molecules :-). Procedure:

1) 100g Black Pepper, refluxed in MeOH for 20 min. Filter, Evap. MeOH to yield
   yellow crystals. Dissolve in Acetone, filter (If needed), then recrystallize
   the Piperine, mp 131øC <- Not bad!

2) Piperine added to NaOH in MeOH. refluxed till MeOH is gone, leaving Sodium
   Piperidiene and Piperic Acid as a Brown tar, crystallizing to yellow gunk
   upon cooling. -100ml dH20 added, solution was heated to boiling. Soln.
   acidified with HCl giving a yellow suspension, and brown oil floating ontop.

3) Solution was cooled, then ugly, chunky, yellow piperic acid was filtered.
   Filter cake was dissolved in acetone, and NaCl filtered out. Recrystallize,
   Note the change of odor.

4) A 1:2:5 oxidation was dreamed, similar to the asarone oxidation. 2.18g
   (.01 Mol) Piperic Acid was suspended (Suspended, it DON'T dissolve) in 150ml
   boiling dH20, containing 4.2g (.05 Mol) Sodium Bicarbonate. To this hot
   solution, 3.16g (.02 Mol) KMnO4 [Well, some didn't dissolve] in 75ml warm
   dH20 added with an eyedropper over about 40 min. (Notes ream an addition
   funnel, or lose your mind from boredom. Keep this slightly exothermic
   reaction CONSTANTLY stirred.)

5) During the additon of the permanganate, she dreamed that the pepperish smell
   subsided almost completely, with the formation of a NEW, milder, marshmallowy
   good smell. Mmmmm. /* The Cook thinks that the oxidation could be done 'on
   the fly', using the smell as an indicator. (If you're good) But last time she
   dreamed that, she oxidized it all into piperonylic acid. OOPS! */

6) The warm brown solution was filtered to leave a slightly yellow/tan solution.
   This was chilled overnight, as per the asarone oxidation, but the crystals
   were TINY! [Actually, this 'failure' has been a reoccurring dream, the main
   cause of the frustration in this rxn]

7) The Cook cursed the slightly cloudy solution, and in a fit of rage, added
   25ml IPA. (To kill any remaining oxidizer) She dumped the solution into a
   pyrex dish, and set it on the heater for a few days.

8) The next time she slept (48h later), she dreamed the solution had evaporated
   into off-white, glassy chunks(YES!!). There was also some brown MnO2 at the
   bottom, and some tartaric acid, but that's not important. What is important
   is: that shit can be filtered/ recrystallized to give just over 1g of
   luscious translucent Piperonal rocks. MP was dreamed to be 41, so it ain't
   Lab Grade, but it ain't bad either, bees. She dreamed this substance had a
   wunnerful, indescribable odor that could be likened to marshmallow with a
   slight fruity, cherry overtone. It smelled so good, she ate it all, and died
   later that day, leaving no evidence or record other than this. So if any bees
   are feeling frisky, she'd like to know HOW BIG it can be scaled. If you dream
   the answer, point your flask towards hell, and yell real loud! ;-)

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Piperonylic acid from Black Pepper:
-----------------------------------
                                   
Preparation of Piperine

One ounce (28 grams) of standard black pepper was placed in a 500 ml flat bottom
flask along with 250ml Everclear to which a condenser was attached to prepare
for standard reflux. With vigorous magnetic stirring, the mixture was refluxed
at just above boiling temperature for 3 hours, allowed to cool, and the mixture
was suction filtered to retrieve the filtrate. Standard distillation
concentrated the filtrate to approximately 20 ml. The concentrated extract was
then added to 20 ml of 10% KOH in Everclear which was heated on a low setting on
a hot plate. To this mixture, water was added dropwise to form a yellow
precipitate until no more precipitate formed. This was suction filtered and
recrystallized with 30 ml of hardware-store acetone made anhydrous by drying
with epsom salts. Yield was approximately 1.3g of crude piperine, which was
stored in a dark place overnight. (approximate because the scale in question was
at best accurate to tenths of grams.) You can do this a couple of times in a
night without much effort, which can effectively yield 2.5 grams.

Hydrolysis of Piperine to Piperic Acid and Piperidine

2 grams of piperine was placed in 20 ml of a 10% KOH in Everclear solution in a
125 ml Erlenmeyer flask and was refluxed using a standard reflux setup for 2
hours. The original article recommends refluxing under reduced pressure, but
there should not be a problem with standard reflux. It's your choice. There is
no shortage of duct tape or chemical burns around these parts, so don't listen
to the author.

The solution was then transferred to a suitable vacuum distillation apparatus
(a 100ml flask would be ideal) and the distillate was collected in an ice cooled
receiving flask. The remaining undistilled residue was scraped out of the
distillation flask and placed in 100 ml of H2O. The solution was acidified with
HcL. The yellow precipitate was vacuum filtered and recrystallized with hot
Everclear to yield approximately 1.5 grams of predominantly piperic acid, which
was confirmed by a melting point of 213 degrees.

Phase Transfer Oxidation Of Piperic Acid

"In a 250 ml two- or three-necked round bottomed flask, place 1.0g of piperic
acid, .1 g of Adogen 464, 10-15 ml of benzene, and a magnetic stirring bar.
Attach a thermometer to the flask through a cork or adapter as well as a small
dropping funnel. Add to this stirred mixture 4.4g of potassium permanganate
dissolved in 50-60 ml of water at such a rate that the reaction temperature
remains below 30 degrees. After all of the potassium permanganate has been
added, stir at room temperature for 90 minutes. Finally, add about 10-20 ml of
saturate sodium bisulfite solution to the reaction mixture and collect the
preciptated manganese dioxide by suction filtration. Wash the precipitate with
10 ml of benzene. Place the filtrate in a separatory funnel, separate the
layers, and wash the benzene layer three times with 10ml of 10% NaOH solution.
Wash the base solution once with 20ml of ether. Carefully acidify the base
solution to pH 1-2 with 6M HcL and extract the acid solution with 3x25ml ether.
Dry the ether solution over magnesium sulfate, filter, and then remove the ether
by use of a rotary evaporator. The yield was approx. .3 grams piperonylic acid."
Obviously, some sort of scale up is necessary to get an amount of product for a
workable synth.

Reference: Page 527 of _Laboratory Experiments In Organic Chemistry_
           by Mohrig and Neckers, no doubt long out of print.

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