Author Topic: pseudo-isodillapiole in Mosla dianthera  (Read 2063 times)

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Vitus_Verdegast

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pseudo-isodillapiole in Mosla dianthera
« on: December 05, 2003, 09:57:00 PM »

Chemical Components of the Whole Herb of Mosla dianthera


Chem. Pharm. Bull. 47(8) 1152—1153 (1999) Vol. 47, No. 8

http://cpb.pharm.or.jp/cpb/199908/C08_1152.pdf



Yueh-Hsiung KUO* and Shu-Ling LIN
Department of Chemistry, National Taiwan University, Taipei, Taiwan, R.O.C.
Received February 17, 1999; accepted May 6, 1999

Abstract:
Extracts of the whole herb of Mosla dianthera were found to contain three new compounds, 4,5-dimethoxy-2,3-methylenedioxy-1-propenylbenzene, 4,5-dimethoxy-2,3-methylenedioxycinnamaldehyde, and 4,5-dimethoxy-2,3-methylenedioxybenzaldehyde together with eleven known compounds, fatty alcohols, 2,4,5-trimethoxybenzaldehyde, a mixture of beta-sitosterol and stigmasterol, betulinic acid, oleanolic acid, ursolic acid, arjunolic acid, beta-sitosteryl glucopyranoside, palmitic acid, myo-inositol, luteolin and rosmarinic acid.

Key words
Mosla dianthera; Labiatae; 4,5-dimethoxy-2,3-methylenedioxy-1-propenylbenzene; 4,5-dimethoxy-2,3-methylenedioxycinnamaldehyde; 4,5-dimethoxy-2,3-methylenedioxybenzaldehyde


There are five species of Mosla genus (Labiatae) indigenous to Taiwan and all of them are herb plants; however, only M. chinensis has had its chemical components investigated.1)
Probably because the species of Mosla genus are scarce, only one other species M. soochowensis2) has been studied. The chemical components included flavones and their glycosides. One of the flavones, mosloflavone1), showed analgesic and antiinflammation effects. This led us to study the chemical constituents of M. dianthera Buch.-Ham. Maxim.

The whole herbs of M. dianthera were extracted with methanol, and the extracts were suspended in water and then
partitioned with chloroform and n-butanol, successively. The chloroform soluble part was subjected to repeated chromatography on silica gel. Fourteen components were isolated, including three new dimethoxymethylenedioxyphenyl derivatives, 4,5-dimethoxy-2,3-methlenedioxy-1-propenylbenzene (1), 4,5-dimethoxy-2,3-methylenedioxycinnamaldehyde (2), and 4,5-dimethoxy-2,3-methylenedioxybenzaldehyde (3), and eleven known compounds, fatty alcohols [mixture of CH3(CH2)nOH, n529, 31, 33, 35], 2,4,5-trimethoxybenzaldehyde (asarylaldehyde)3), steroidal mixtures ( beta-sitosterol and stigmasterol)4), betulinic acid5), oleanolic acid6), ursolic acid6), arjunolic acid7), beta-sitosteryl glucopyranoside8), myo-inositol9), luteolin4), and rosmarinic acid10)
The known compounds were identified through comparison of their IR, MS, and NMR spectra with anthentic samples or with value taken from the literature. In this paper, we report structure of three new compounds.

The molecular formula of 1 was determined as C12H14O4 by HR-EI-MS. Analysis of the IR spectrum of 1 suggested it contained an aromatic group (3045, 1601, 1490 cm-1), transconjugated double bond (1628, 958 cm-1) and a methylenedioxy group (2837, 1230, 1064, 927 cm-1). The 1H-NMR spectrum exhibited signals for one vinyl methyl group at d 1.86 (dd, J56.6, 1.7 Hz), two singlet phenolic methyl groups at d 3.84 and 3.85, a singlet methylenedioxy group at d 5.93 (2H), two trans-olefinic protons at d 6.09 (dq, 1H, J515.7, 6.6 Hz) and 6.57 (dq, 1H, J515.7, 1.7 Hz), and a singlet phenyl proton at d 6.54. The UV absorption at lmax 246 and 288 nm suggested compound 1 has an double bond conjugated with aromatic group. Six aromatic carbon signals exhibited at d 104.4, 124.6, 135.6, 135.7, 138.9, and 139.5. The signal at d 104.4 (CH) is assigned as a substituted free aromatic carbon and ortho to oxygenated carbon. And the signal at d 124.6 (C) was considered to be linking to the 1-propenylgroup and vicinal to oxygenated carbon. The other four phenyl carbons are higher field than d 140; this result indicates that the four oxygenated phenyl carbons are contiguous.

Therefore three possible structures (1, 4, and 5) for compound 1 were proposed. The correct structure of 1 was confirmed by chemical transformation and spectral evidence.

Hydrogenation of compound 1 under catalytic hydrogenation conditions with Pd/C as catalyst in methanol solution gave compound 6 [liquid; d 0.91 (t, 3H, J57.2 Hz), 1.54 (sex, 2H, J57.2 Hz), 2.48 (t, 2H, J57.2 Hz), 3.82, 3.85 (s, each 3H), 5.90 (s, 2H), and 6.27 (s, 1H)]. The relative position was elucidated by NOE evidence (see structure 6). Irradiation of the phenyl proton at d 6.27 afforded an nuclear Overhauser effect (NOE) at the benzyl proton ( d 2.48) (5.7% enhancement) and one of the methoxy groups ( d 3.82) (10.7% enhancement).
And irradiation of the signal at d 2.48 gave only an NOE to the phenyl proton ( d 6.27, 5.2% enhancement). The above evidence determined the structure of 1 as 4,5-dimethoxy-2,3-methylenedioxy-1-propenylbenzene. This is the first time that compound 1 has been isolated from nature though the same compound had been prepared from compound 7 by basic isomerization11).

Compound 2 was isolated as a needle crystal (mp 140—142°C), and showed the molecular formula C12H12O5, based on HR-EI-MS. The IR spectrum of 2 showed the presence of an aromatic group and a conjugated carbonyl system. The 1H-NMR spectrum of 2 is very similar to that of 1 indicating the presence of a methylenedioxy group [ d 6.02 (s, 2H)], two phenolic methyl groups ( d 3.86, 3.97), and a phenyl proton [ d 6.71 (s, 1H)]. It also contained two trans-olefinic protons [ d 6.63 (dd, 1H, J515.9, 7.7 Hz), 7.69 (d, 1H, J515.9 Hz)], and one aldehyde proton [ d 9.62 (d, J57.7 Hz)]. The above spectrum indicated 2 has an aldehyde group conjugated with an olefinic group instead of a methyl group in 1. The longer wave length absorptions of UV spectrum at lmax 234, 249, and 335 nm further proved the assignment. The phenyl proton ( d 6.71) showed an NOE with a methoxy group ( d 3.86) and an olefinic proton ( d 7.69); this decided the structure of compound 2 as 4,5-dimethoxy-2,3-methylenedioxycinnamaldehyde. The 13C-NMR data also agreed to the assigned structure.

Compound 1 was oxidized with selenium dioxide in dioxane under reflux to yield a product, which was identified as compound 2.

Aldehyde 3 melted at mp 106—108 °C with formula C10H10O5 based on HR-MS. Its IR spectrum indicated aromatic (1590, 1497 cm-1) and conjugated carbonyl groups (1655 cm-1). The 1H-NMR signal at d 10.21 (s) in addition to the UV absorption bands at lmax 230 and 301 nm indicated an oxygenated benzaldehyde functionality. The 1H-NMR signals presented a singlet phenyl proton at d 7.06, a  methylenedioxyl group at d 6.07 (s, 2H), and two phenolic methyl groups at 3.86 and 4.03. Four contiguous oxygenated aromatic carbons were discernible from the 13C-NMR signals at d 138.1, 139.8, 142.2, and 143.1. NOE correlation of aldehyde 3 is shown in structure 8, which confirmed the structure of 3 as 4,5-dimethoxy-2,3-methylenedioxycinnamaldehyde.

Reduction of 3 with sodium borohydride in methanol produced alcohol 9 [amorphous; 3305 cm-1; d 4.57 (s, 2H, –CH2OH) and 6.46 (s, 1H, phenyl H)].

Aldehyde 3 could be prepared from 1 by oxidation with osmium tetraoxide and sodium periodate in dioxane. Aldehyde 3 had been synthesized by Dallacher12), but this is the first time thus isolated from a natural source.


Experimental
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. Optical rotations were measured with a JASCO DIP-4 polarimeter. 1H- and 13C-NMR spectra were run on a Brucker AM 300 in CDCl3 solution with tetramethylsilane (TMS) as internal standard.
Chemical shifts are given in hertz (Hz). EI-MS and UV spectra were taken on a JEOL-JMS-100 and Hitachi RMS-4 spectrometer, respectively.

Extraction and Isolation
Air-dry whole herb of Mosla dianthera (4.4 kg) was extracted with MeOH (60 l) at room temperature three times (6 d each time). The crude extracted was evaporated in vacuo to leave a black syrup (400 g), and then water was added to a total volume of 1.3 l. The aqueous layer was partitioned with CHCl3 (1l x3) and n-BuOH (1l x3), successively. The weight of the CHCl3 extract was about 230 g, and a portion of this residue (120 g) was subjected to repeated chromatography on silica gel. The eluent solvent system was a combination of hexane and ethyl acetate.

The components were eluted in order as 1 (90 mg), 2 (20 mg), and 3 (10 mg) (5% EtOAc in hexane), fatty alcohol [CH3(CH2)nOH, n529, 31, 33, 35; 30 mg], 2,4,5-trimethoxybenzaldehyde (110 mg), and steroidal mixture ( beta-sitosterol and stimasterol, 800 mg) (10% EtOAc in hexane), betulinic acid (100 mg), oleanolic acid (150 mg), and ursolic acid (120 mg) (20% EtOAc in hexane), arjunolic acid (80 mg) (80% EtOAc in hexane), beta-sitosteryl glucopyranoside (300 mg) (EtOAc), luteolin (20 mg) (from 5% MeOH in EtOAc), rosmarinic acid (10 mg) (10% MeOH in EtOAc), and myo-inositol (150 mg) (30% EtOAc in MeOH).

4,5-Dimethoxy-2,3-methylenedioxy-1-propenylbenzene (1) mp 56—57 °C. UV lmax MeOH nm (log e): 246 (4.36), 288 (4.00). IR (KBr) cm-1: 3045, 2837, 1628, 1601, 1490, 1230, 1064, 958, and 927. 13C-NMR (CDCl3) d: 18.7, 56.7, 60.3, 101.6, 104.4, 124.6, 124.9, 125.4, 135.6, 135.7, 138.9, 139.5. EI-MS (70 eV) (rel. int.) m/z: 222 (M1, 100), 207 (11), 177 (23), 149 (27). HR-EI-MS m/z: 222.0892 (M1, Calcd for C12H14O4: 222.0895).

4,5-Dimethoxy-2,3-methylenedioxycinnamaldehyde (2) mp 140—142 °C, UV lmax MeOH nm (log e): 234 (4.15), 249 (4.18), 335 (4.27). IR (KBr) cm21: 3035, 1683, 1615, 1600, 1500, 1352, 1242, 1188, 1116, 1064. 13CNMR (CDCl3) d: 56.8, 60.3, 102.4, 106.9, 120.1, 127.8, 138.2, 138.6, 139.6, 140.1, 147.5, 194.1. EI-MS (70 eV) (rel. int.) m/z: 236 (44), 205 (89), 182 (66), 140 (100), 139 (54), 127 (18), 110 (54). HR-EI-MS m/z: 236.2243.(M1, Calcd for C12H12O5: 236.2245).

4,5-Dimethoxy-2,3-methylenedioxybenzaldehyde (3) mp 106—108 °C; UV lmax MeOH nm (log e): 230 (4.15), 301 (3.90). IR (KBr) cm21: 3041, 1655, 1590, 1497, 1237, 1045. 13C-NMR (CDCl3) d: 55.5, 60.6, 102.7, 106.0, 122.2, 138.1, 139.8, 142.2, 143.1, 187.8. EI-MS (70 eV) (rel. int.): m/z 210 (100), 195 (30), 181 (12), 164 (23); HR-EI-MS m/z: 210.0528 (M1, Calcd for C10H10O5: 210.0531).


Catalytic Hydrogenation of 1
A solution of 1 (20 mg) in 10 ml of MeOH was hydrogenated in the presence of 10% Pd/C (5 mg). After 5 h, the catalyst was removed by filtration and washed several times with MeOH. The combined filtrate and washings gave a product 6 (19 mg): liquid, IR (KBr) cm-1: 3037, 1630, 1610, 1495, 1260, 1150, 1185, 1075, 960.

Selenium Dioxide Oxidized Compound 1 to Produce 2
Selenium dioxide (22.5 mg) was added to a solution of 1 (45 mg) in dioxane (1.2 ml). The reaction mixture was heated under reflux for 4.5 h. The reaction mixture was cooled to ambient temperature, and then 30 ml of H2O was added. The reaction mixture was extracted with Et2O (20 ml x3) to yield a solid which was purified to afford compound 2 (20 mg).

Reduction of 3 with NaBH4 in MeOH
Excess NaBH4 (10 mg) was added in small portion to a solution of 3 (20 mg) in MeOH (2 ml), and the reaction mixture was stirred for 30 min. The reaction mixture was diluted (15 ml 1 : 1 of EtOAc : hexane) and washed with H2O (10 ml x3). Evaporation of the organic layer under reduced pressure gave a residue that was chromatographed on SiO2 to produce 9 [amorphous; IR (KBr) nmax cm-1: 3305, 1610, 1500, 1145. 1H-NMR (CDCl3) d: 3.46 (s, 1H, –OH), 3.84, 3.94 (s, each 3H), 4.57 (s, 2H, H-7), 5.94 (2H, m), 6.46 (s, 1H, H-6)].

Oxidation of 1 with OsO4 and NaIO4 in Dioxane
Compound 1 (20 mg) was dissolved in a mixture of dioxane (1.2 ml) and H2O (0.4 ml), and then a catalytic amount of OsO4 (5 mg) was added. After 30 min, the oxidizing agent NaIO4 (60 mg) was added, and then stirred at room temperature for 3 h. The reaction mixture was poured into 50 ml of water, and then the aqueous solution was extracted with ether (30 ml) three times. After purification on silica gel, the product (12 mg) was identified as 3.


Acknowledgments
We thank the National Science Council of the Republic of China for financial support.

References
1) Zheng S., Sun L., Shen X., Indian J. Chem. Sect. B, 35, 392—394 (1996).
2) Wu F. W., Cheng P. S., Chou P. N., Sung K. C., Yao Hsueh Tung Pao, 18, 16—19 (1981).
3) Jacobson M., Lloydia, 39, 412—415 (1976).
4) Lin Y. L., Tsai W. J., Chen I. S., Kuo Y. H., J. Chin. Chem. Soc., 45, 213—217 (1998).
5) Kuo Y. H., Li Y. C., J. Chin. Chem. Soc., 44, 321—327 (1997).
6) Kuo Y. H., Chen Z. S., Lin Y. L., Chem. Pharm. Bull., 44, 429—436 (1996).
7) Lewis K. G., Tucker D. J., Aust. J. Chem., 36, 2297—2305 (1983).
8) Kuo Y. H., Yeh M. H., J. Chin. Chem. Soc., 44, 379—383 (1997).
9) Dorman D. E., Angyal S. J., Robert J. O., J. Am. Chem. Soc., 92, 1351—1354 (1970).
10) Lee S. M., Lai J. S., Kuo Y. H., Chem. Express, 7, 887—900 (1992).
11) Burke B., Nair M., Phytochemistry, 25, 1427—1430 (1986).
12) Dallacher F., Chem. Ber., 102, 2663—2676 (1969).


Vitus_Verdegast

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DMMDA-3, a new "Essential Amphetamine"
« Reply #1 on: December 05, 2003, 10:23:00 PM »
Looks like we have a new ring substitution pattern to add to the collection of essential amphetamines. The 2,3-methylenedioxy-4,5-dimethoxy pattern of pseudo-isodillapiole will give rise to 2,3-methylenedioxy-4,5-dimethoxyamphetamine, the Eleventh Essential Amphetamine, and (as far as I know) of unknown activity.

http://www.erowid.org/library/books_online/pihkal/pihkal157.shtml






The unknown ones will certainly be called DMMDA-3, -4, -5 and -6, but the assignments of code to structure haven't even been thought out yet

http://www.erowid.org/library/books_online/pihkal/pihkal059.shtml



Since the good doctor has left the nomenclature of the four other possible isomers of DMMDA an open question, I guess I can take the liberty of assigning the name DMMDA-3 to this new "Essential Amphetamine".


I highly doubt that the essential oil of this rare species will be commercially available, but the corresponding allylbenzene can be synthesized from sesamol (3,4-methylenedioxyphenol) as described in:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pseudodillapiole.html






GC_MS

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Pseudodillapiole
« Reply #2 on: December 08, 2003, 03:42:00 PM »
Pseudodillapiole can also be found in Piper aduncum, P fadyenii and P hispidum. See

Post 474245

(GC_MS: "What's in my Piper?", Chemicals & Equipment)
. One of the references (B Burke et al. Phenylpropene, benzoic acid and flavonoid derivatives from fruits of Jamaican Piper species. Phytochemistry 25(6) (1986) 1427-1430) is worth looking into...

Shulgin's list of Essential Amphetamines is pretty redundant, but that is not his fault. For instance, Piper marginatum, a common plant in Paraiba (Brazil), is known to contain 2,4,6-trimethoxypropenylbenzene (pseudo-TMA2) aka pipermargine. There are so many new phytochemical discoveries every year that your list of Essential Amphetamines needs frequent updating  ;)


Rhodium

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Syntheses of Dillapiole & its 4-Methylthio analog
« Reply #3 on: December 18, 2003, 09:41:00 PM »
New syntheses of dillapiol [4,5-dimethoxy-6-(2-propenyl)-1,3-benzodioxole], its 4-methylthio and other analogs
Sherry L Majerus,  Najma Alibhai,  Sasmita Tripathy,  Tony Durst

Canadian Journal of Chemistry, Vol. 78(10), 1345-1355 (2000)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/dillapiole.analogs.html)

Abstract
Three syntheses of the natural synergist dillapiol from the natural, commercially available sesamol as starting material, are described. A major difference between these is the order of introduction of the additional methoxy and allyl substituents. In one of the syntheses, a formyl group is introduced at C4 via an electrophilic aromatic substitution reaction and then converted into the methoxy group using a Baeyer-Villiger reaction and subsequent methylation; in the other two, a directed ortho-metalation, Baeyer-Villiger, methylation sequence was employed. Various intermediates along the synthetic route were used to generate more than 30 analogs, including the 4-thiomethyldillapiol, to investigate the structure activity relationships of the pesticide synergism of these compounds.
____ ___ __ _

Cognate preparations:

Post 413969

(Vitus_Verdegast: "Synthesis of dill-apiole & tetraMeO-allylbenzene", Novel Discourse)

Post 477701

(Rhodium: "Synthesis of all Apiole Positional Isomers", Novel Discourse)


Sesamol can be synthesized by performic oxidation (Bayer-Villiger) of Piperonal:

Patent US5840997

(Example 2: 94% crude yield, 78% distilled)


Saddam_Hussein

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sesamol
« Reply #4 on: December 20, 2003, 05:40:00 PM »
It depends on what syntheses you exactly bear in mind, but there might be a more OTC way to obtain these "apiolic amphetamines".

You can convert piperonal to sesamol, use the latter in a Claisen rearrangement and methylate (ethylate?) the thus obtained phenol. You know have asaricin. You can oxidize this compound to the benzaldehyde and further to the phenol. You could, however, also methylate sesamol and subject it to a Vilsmeier-Haack formylation, and oxidize the thus obtained benzaldehyde to a phenol.

Whatever you do, the weak point in this synthesis is "piperonal". In the Old Days, Saddam imported several trucks with sassy on a daily basis via his good friends and businesspartners residing in China, but ever since the Evil A******** occupied the country and installed DEA Baghdad, this is not possible anymore. However, inventive and creative as we are, we thought of the following plan:

2-hydroxy-5-methoxybenzaldehyde - This compound can be obtained via the Reimer-Tiemann formylation of 4-methoxyphenol. This method is pretty OTC and several references for this method can be found on Rh's site and via TFSE as well. Even in my desert rat bunker (no, that was by double you cought in Tikrit; the CIA cheated with the DNA materials), my chemists are able to obtain 60-65% yields of the pure product.

1,2-dihydroxy-5-methoxybenzene - The previously described benzaldehyde can be subjected to the Dakin reaction to yield 1,2-dihydroxy-5-methoxybenzene. I have performed Kabalka's SPC Dakin reaction (

https://www.thevespiary.org/rhodium/Rhodium/chemistry/dakin.html

) but did not isolate the end product. However, there clearly was a reaction going on: the reaction mixture immediately coloured a brownish red and became warm to the hand.

The isolated 1,2-dihydroxy-4-methoxybenzene could be methylenated (DCM, DBM) to obtain the methyl ether of sesamol. Formylation with POCl3 and DMF shouldn't be a problem.

It's a shame my scientists did not further isolate the 1,2-dihydroxy-4-methoxybenzene. Maybe I shouldn't have told them to put all their efforts on sarin derivatives  ::) . However, I think the proposed syntheses are straightforward, and do form an alternative to not OTC piperonal.


Rhodium

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Sesamol (3,4-Methylenedioxyphenol) from Piperonal
« Reply #5 on: October 21, 2004, 01:07:00 AM »
Synthesis of Sesamol by Bayer-Villiger Oxidation of Piperonal using m-CPBA
Ind. J. Chem. 22B, 1150 (1983)

Summary
Piperonal (I) on treatment with m-chloroperbenzoic acid followed by hydrolysis of intermediate formate ester affords 3,4-methylenedioxyphenol (II).



Rapoport [J. Org. Chem. 44, 2153 (1979)] while synthesising the halojuglones, successfully used m-chloroperbenzoic acid for the conversion (80%) of a carbonyl group into a hydroxyl group. Similar oxidation of piperonal (I) by m-chloroperbenzoic acid afforded the intermediate formate ester in 95% yield. The latter on treatment with dil. HCl in MeOH-THF (1:1) gave II in 75% overall yield.

3,4-Methylenedioxyphenol (II)

A mixture of piperonal I (1 g) and m-chloroperbenzoic acid (2.4 g) in methylene chloride (30 ml) was stirred for 21 hr and to this was added aq. sodium thiosulphate (10%, 15 ml) and the reaction mixture further stirred for 45 min. Another portion of aq. sodium thiosulphate (10%, 15 ml) was added and the reaction mixture stirred vigorously for 10 min. The organic layer was collected and the aqueous layer extracted with methylene chloride (2x25 ml), the organic extracts combined and washed successively with aq. sodium thiosulphate (10%, 2x50 ml), brine (15%, 2x50 ml) and dried (Na2SO4). On concentration a brown coloured intermediate formate ester (900 mg) was obtained. The above ester was taken in MeOH-THF (1:1, 25 ml), prepared from freshly distilled solvents, and cooled to 10°C in an ice-bath. Pre-cooled methanolic KOH (10%, 8 ml) was added with shaking in two instalments and the contents kept at 10°C for 30 min. Ice-cold HCl (5%, 15 ml) was added to the solution in three instalments with shaking. The reaction mixture changed its colour and acquired pH of ~1.0. It was extracted with methylene chloride (3x25 ml), washed with water (2x25 ml) and brine (2x25 ml) and dried (Na2SO4). On removing the solvent under reduced pressure fine needle shaped crystals of II, mp 65-66°C (750 mg), were obtained.


phenethyl_man

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Re: Sesamol can be synthesized by performic...
« Reply #6 on: October 24, 2004, 03:33:00 PM »

Sesamol can be synthesized by performic oxidation (Bayer-Villiger) of Piperonal: Patent US5840997 (Example 2: 94% crude yield, 78% distilled)



Yes, but 5 liters of internal volume and 1.65 L of CH2Cl2 required for 50 grams of piperonal?  ..or is this just another case of chemists with corporate sponsorship having fun w/expensive solvents?  ;)