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Safrole - Synthesis & Reactions (Beilstein Crossfire search)

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A Study of the Precursors, Intermediates and Reaction Byproducts in the Synthesis of MDMA

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Abstract

3,4-Methylenedioxymethylamphetamine (MDMA) was prepared by three synthetic routes. Analytical data from thin-layer chromatography, gas chromatography and gas chromatography-mass spectrometry of the precursors (safrole and isosafrole), intermediates (isosafrole glycol, piperonylmethylketone, N-formyl-3,4-methylenedioxymethylamphetamine, N-formyl-3,4-methylenedioxyamphetamine and 1-(3,4-methylenedioxyphenyl)-2-bromopropane), reaction by-products and the product MDMA were obtained. Further analyses of MDMA using other techniques including ¹H- and ¹³C-nuclear magnetic resonance spectroscopy, X-ray diffraction, infrared spectroscopy, ultraviolet spectroscopy and high performance liquid chromatography were also carried out. The results were then used as reference data for the identification of MDMA in case samples and also to establish the route of synthesis of illicitly prepared MDMA by the study of trace impurities.

Introduction

Fig. 1.
Diagram of the synthetic routes investigated.
Route I: PMK → N-formyl-MDMA → MDMA
Route II: PMK → N-formyl-MDA → MDMA
Route III: safrole → MDPBP → MDMA.

Although patented in 1914 as an appetite suppressant¹, 1-(3,4-methylenedioxyphenyl)-2-(N-methylamino)- propane, more commonly known as 3,4-methylenedioxymethylamphetamine (MDMA or Ecstasy), is a relatively new drug of abuse in the UK. Over the last 4 years, the number of seizures of the drug has increased and already, illicit laboratories for the production of MDMA have been uncovered. There is no current therapeutic use for MDMA in the UK and under British legislation, it is controlled as a class 'A' drug by the Misuse of Drugs Act, 1971, as amended by the Misuse of Drugs Act, 1971 (Modification) Order, 1977.
MDMA in illicit preparations was first observed in 1972 (Gaston, T.R. and Rasmussen, G.T. pers. commun.) and various aspects of this drug have been reviewed^2,3. However, there is only limited information on the forensic examination of the various methods of illicit manufacture. Verweij⁴ examined the reaction mixtures of MDMA prepared by low pressure reductive amination. A number of impurities were identified by gas chromatography-mass spectrometry (GC-MS). The analyses by GC-MS of samples from a clandestine laboratory involved in the synthesis of MDMA from sassafras oil was carried out by Noggle et al.⁵. Lukaszeweski⁶ made a study of the various syntheses of 3,4-methylenedioxyamphetamine (MDA) where the precursors, intermediates and reaction by-products were characterised by chromatographic and spectroscopic techniques.
This study was designed to obtain analytical data pertaining to the identification of precursors, intermediates and reaction by-products encountered in certain synthetic routes as well as obtaining further analytical information to assist in the laboratory identification of MDMA.

Experimental

Materials

Safrole (97%), N-methylformamide (NMF, 99%) and trifluoroacetic anhydride (TFAA) were purchased from Aldrich Chemical Co. (Gillingham, Dorset, UK); isosafrole (cis and trans, 95%) and methylamine (33% in ethanol) were obtained from Fluka Chemical Co. (Glossop, UK); formamide and lithium aluminium hydride (LAH) were from Cambrian Gases (Croydon, UK). Other reagents, solvents (general purpose reagent grade) and methanol (Analar grade) for high-performance liquid chromatography (HPLC) were obtained from BDH Ltd (Poole, UK).

Syntheses

Fig. 1 shows a summary of the syntheses of which Routes I and II involve the Leuckart reaction^7,8. The original synthesis of MDMA¹ was carried out by Route III. Piperonylmethylketone (PMK) was synthesized from isosafrole through the intermediate isosafrole glycol⁶.
Route I.
Formic acid (3.66 g), NMF (7.6 g) and PMK (9.0 g) were refluxed at 150—170°C for 7 h with additional formic acid (7.32 g) added periodically. On cooling, a clear yellow solution of N-formyl-3,4-methylenedioxymethylamphetamine (N-formyl-MDMA) was obtained. Concentrated hydrochloric acid (30 ml) was added to this solution which was refluxed for a further 3 h. The reaction mixture was made basic with sodium hydroxide and the crude MDMA extracted into diethyl ether. After the volume of the organic solvent was decreased, the remaining residue was treated with hydrogen chloride gas to yield a gelatinous brown precipitate of impure MDMA hydrochloride. The crude salt, dissolved in boiling methanol, was added to chilled acetone to form a crystalline product. This was recrystallized to yield fawn crystals with a melting point of 147—148°C⁹.
Route II.
Formamide (65 g) and PMK (23 g) were refluxed at 190°C for 5 h. The solution was made basic and extracted with diethyl ether. The ethereal solution was first washed with dilute sulphuric acid, rinsed with water and finally dried over anhydrous sodium sulphate. The diethyl ether volume was reduced to yield a clear yellow solution of N-formyl-3,4-methylenedioxyamphetamine (N-formyl-MDA). This was added drop-wise to LAH (2.5 g in 100 ml of sodium-dried diethyl ether) and refluxed for 3 h. The excess LAH was decomposed by the addition of water and the resulting mixture was filtered and the precipitate washed with diethyl ether. The washings and the filtrate were combined and extracted with dilute sulphuric acid. The aqueous solution was made alkaline with dilute sodium hydroxide and extracted with diethyl ether. The solvent was evaporated leaving an amber oil of crude MDMA.
Route III.
The reactions described in the Merck patent¹ involve the formation of 1-(3,4-methylenedioxyphenyl)-2-bromopropane (MDPBP) from safrole followed by reaction with methylamine. This was the method followed.
Extraction of intermediates and reaction by-products
Route I. An aliquot of the acidic N-formyl-MDMA reaction mixture was washed with diethyl ether, made basic with dilute sodium hydroxide and extracted with diethyl ether. This sample was analysed by thin-layer chromatography (TLC), gas chromatography (GC) and GC-MS.
Route II. A sample of the N-formyl-MDA reaction mixture was made acidic with tartaric acid¹⁰ and extracted with diethyl ether. The organic layer was separated and extracted with dilute hydrochloric acid. The acidic extract was then made basic with dilute sodium hydroxide and extracted with chloroform. This sample was analysed by the above-mentioned methods.
Route III. A sample of the chloroform used to extract the brominated intermediate from the safrole/hydrobromic acid reaction mixture was analysed by the techniques described above.
Preparation of the trifluoroacetyl (TFA) derivative
Ethyl acetate (1.0 ml) and TFAA (0.1 ml) were added to a 10-ml screw-topped tube containing the dried extract. The reaction mixture was heated at 60°C for 20 min, evaporated to dryness and methanol (0.1 ml) was added to the tube prior to GC-MS analysis.
Extraction of impurities from case samples
Powder or crushed tablet (5 mg), known to contain the MDMA salt, was vortex-mixed with redistilled diethyl ether (1 ml) and centrifuged. The supernatant was taken off, evaporated to dryness and methanol (0.1 ml) was added prior to GC-MS analysis.

Analytical techniques

HPLC

The two HPLC systems used 12.5 cm by 4.9 mm (i.d.) stainless steel columns with slurry packed 5 µm Spherisorb silica (Phase Separations, Queensferry, UK) and an eluent flow rate of 2 ml/min.
System I. A reciprocating pump, type HM (Metering Pumps, London, UK), delivered the eluent of methanol/30% hydrochloric acid/ammonium hydroxide (d. 0.880) 2000:5.8:18.4. The sample in 0.02 M methanolic hydrochloric acid was introduced to a Rheodyne model 7125 injection valve (Berkeley, CA, USA) fitted with a 5-µl loop. A Cecil CE212 UV detector (Cecil Instruments, Cam-bridge, UK) monitored the eluant by absorption at 284 nm.
System II. An Applied Chromatography Systems model 400 pump (ACS Ltd., Macclesfield, UK) delivered the eluent of 0.01 M ammonium perchlorate in methanol adjusted to pH 6.7 by the addition of 1 ml/l of 0.1 M sodium hydroxide in methanol. The sample in methanol was introduced to a Rheodyne injection valve, model 7125, fitted with a 20-µl loop. A LDC spectromonitor III (LDC Analytical Ltd., Stone, UK) monitored the eluant by UV absorption at 284 nm.

GC-MS

A VG 12-12F quadrupole mass spectrometer (VG Biotech, Altrincham, UK) was used in combination with a Carlo Erba model 4160 gas chromatograph (Fisons Instruments, Crawley, UK). The inlet of a fused-silica capillary column of bonded dimethyl silicone (15 m by 0.22 mm i.d., 0.25 µm film thickness; Thames Chromatography, Maidenhead, UK) was connected to a split/splitless injector. The column outlet was inserted directly into the ion source of the mass spectrometer. A splitless injection was made with the GC oven temperature held at 100°C for 1 min. The temperature was ramped at 30°C/min to 280°C where it was maintained for 5 min. The temperature of the injection port and the transfer line was 270°C. The inlet pressure for the helium carrier gas was 1.0 kg/cm-2. The mass spectrometer was used in the EI mode, the source temperature was 200°C and electron energy was 70 eV. Mass spectra were obtained by scanning from 35 to 535 amu at 1 s/scan and the data was processed on a VG DS2050 Data System (VG Analytical, Manchester, UK). Isobutane was the reagent gas in the chemical ionization (CI) mode and the source temperature was 200°C. The vacuum in the source housing was 10-4 Torr and the mass spectrometer scanned from 100 to 400 amu at 1 s/scan.

Other techniques

Ultraviolet (UV) spectra were recorded on a Uvikon UV/visible spectrophotometer, model 810 (Kontron Scientific Instruments Ltd., St Albans, UK). Infrared (IR) spectra were obtained as potassium bromide discs on a Perkin Elmer IR spectrophotometer, model 298, used in conjunction with a Perkin Elmer IR data station 3600 (Perkin Elmer Instruments, Beaconsfield, UK). The other techniques are detailed with their tabulated data.

Results and Discussion

MDMA and intermediate compounds

There is a large number of potential synthetic routes to MDMA² but the choice of this study was restricted to three. From the information available, it appears that the Leuckart reaction (Routes I and II) is the most commonly used reaction in the illicit production of amphetamine type drugs. This reaction can be easily adapted to the manufacture of methylenedioxy-substituted analogues. The reactions (Route III) described in the Merck patent¹ could be used for those in search of a published method.
The IR, UV and ¹H-MMR spectra were all consistent with those published previously^9,13. The ¹³C-NMR spectra (both broad-band proton decoupled (BBPD) and single frequency off-resonance decoupled (SFORD) spectra) and the XRD pattern of MDMA·HCl are presented in Fig. 2 and Tables 1 and 2 respectively. Fig. 3 and 4 show the mass spectra of N-formyl-MDMA and MDPBP. The mass spectra of safrole, isosafrole, isosafrole glycol, PMK, N-formyl-MDA and MDMA have been reported previously^6,9. The mass spectrum of MDMA is not highly characteristic. It has a base peak of mass 58 with minor ions of mass 135 and 136¹⁴. A highly characteristic mass spectrum can be obtained with the TFA derivative. Fig. 5 shows the mass spectrum and proposed fragmentation route. The chromatographic data for MDMA and related compounds by TLC, GC and HPLC are shown in Tables 3, 4 and 5, respectively.

Reaction by-products

Route I.

A reaction by-product N,N-dimethyl-3,4-methylenedioxyamphetamine (DMMDA) was identified. This assignation was based on the mass spectrum shown in Fig. 6 together with a molecular weight of 207 (from the CI mass spectrum) and by analogy with the corresponding amphetamine synthesis^11,12. However, DMMDA (a tertiary amine) has the same mass spectrum as its isomer N-ethyl-3,4-methylenedioxyamphetamine (a secondary amine)^13,14. The compound did not, however, form a derivative with TFAA, showing it to be a tertiary amine and not a secondary amine. This compound could be the product of the reaction of dimethylformamide (DMF) and PMK where DMF is an impurity of NMF¹². Verweij⁴ has identified DMMDA as an impurity in illicit MDMA manufactured by low pressure reductive amination.

Route II.

Reaction by-products such as [1-(3,4-methylenedioxyphenyl)-2-propyl]amine and [1-(3,4-methylenedioxyphenyl)-2-propyl]methylamine which have been identified in the synthesis of MDA⁶ using the Leuckart reaction were not observed in this study. However, GC-MS provides some evidence to suggest the presence of methylenedioxy substituted pyrimidines and pyridines analogous to those observed in the cognate synthesis of amphetamine^10,15. The mass spectrum of the tentatively substituted pyrimidine (Fig. 7a) is characterized by its two major ions of mass 213 and 214. The molecular ion of mass 214 exhibits a mass shift of 44 from that observed in the mass spectrum of the cognate amphetamine impurity¹⁵, suggesting a methylenedioxy substituted analogue. Similarly, the molecular ion of mass 348 (Fig. 7b) of the tentatively identified substituted pyridine impurity¹⁰ exhibits a mass shift of 88 with respect to similar compounds observed in amphetamine synthesis. This suggests a methylenedioxy doubly substituted pyridine analogue which is consistent with the structure of the known impurity.
No significant reaction by-products were identified in Route III which involves the formation of the intermediate MDPBP.

Applications

Impurities are often observed in illicitly prepared drugs samples as they are not usually purified to any great degree after manufacture. In the case of illicitly prepared amphetamine, the presence of 'route specific' impurities is used to establish the manufacturing process¹¹. Applying this analogy to MDMA, the identification of the reaction intermediates in the illicit sample can be used to establish the synthetic route used. Figure 8 shows the chromatogram of an extract of a typical sample. The reaction intermediates isosafrole glycol, PMK and N-formyl-MDMA were observed together with the reaction by-product DMMDA. This demonstrates that route I was used in the manufacture.

Conclusion

In addition to providing reference data for the identification of MDMA in case samples, the analytical data from this study can be used to determine the synthetic route used in the illicit manufacture of MDMA, and may also help in the discrimination of sources of origin in the comparison of illicit samples.

Table 4
GC Data for MDMA and Related Compds.

Compound	Relative retention time
(MDMA = 1.0)
Safrole	0.35
trans-Isosafrole	0.44
cis-Isosafrole	0.53
PMK	0.97
DMMDA	1.21
MDPBP	1.44
Isosafrole glycol	2.24
N-formyl-MDA	5.77
N-formyl-MDMA	6.45

GC was performed using a glass column
(2 m x 6 mm o.d.) packed with 3% OV17
coated on GasChromQ (Phase Sep.,
Queensferry, UK) with a N₂ carrier gas
flow rate of 30 ml/min. The Philips
PU4500 gas chromatograph was fitted
with a flame ionization detector. The
oven temp was 200°C isothermal,
injector temp was 200°C and the
detector temp was 280°C.

Table 1
Data From ¹³C-NMR Spectra of MDMA·HCl

Chemical shift ^{(BBPD, Fig. 2a)}	Multiplicity ^{(SFORD, Fig. 2b)}	Assignment
15.4	quartet	C-2
30.2	quartet	C-1
39.1	triplet	C-4
57.3	doublet	C-3
101.2	triplet	C-9
108.7	doublet	C-11
109.6	doublet	C-7
122.6	doublet	C-6
129.8	singlet	C-5
146.9	singlet	C-8
148.1	singlet	C-10

Table 3
TLC Data for MDMA and Related Compounds

Compound	Relative Retention Value
MDMA	0.27
DMMDA	0.38
N-formyl-MDA	0.75
N-formyl-MDMA	0.78

TLC was carried out on glass plates coated
with Kieselguhr 60 F254 (Merck TLC plates,
BDH Ltd., Poole, UK) that had been dipped
in a methanolic solution of 0.01 M sodium
hydroxide¹⁶. The plates were developed
in a methanol/acetone (3:1) solvent system,
visualised in ultraviolet light (254 nm) and
sprayed with acidified iodoplatinate solution.

Table 2

XRD Pattern of MDMA·HCl

Fig. 2. The ¹³C NMR spectra of MDMA.HCl. (a) BBPD and (b) SFORD.
Fig. 3. The mass spectrum of N-formyl-MDMA.
Fig. 4. The mass spectrum of MDPBP.
Fig. 5. The mass spectrum of the MDMA·TFA derivative and the proposed fragmentation pathway.
Fig. 6. The mass spectrum of DMMDA.
Fig. 7. Mass spectra of (a) substituted pyrimidine and (b) substituted pyridine.
Fig. 8. Total ion chromatogram of illicitly prepared MDMA and impurities. A: PMK; B: MDMA; C: DMMDA; D: isosafrole glycol; E: N-formyl-MDMA. A VG 15—250 quadrupole mass spectrometer, fitted with a Hewlett Packard 5980 gas chromatograph (Hewlett Packard Analytical, Winnersh, UK), was used in the analysis of extracts of case samples. The operating conditions were in the EI mode as described earlier.

References

E. Merck, Verfahren zur Darstellung von Alkyloxyaryl-, Dialyloxaryl- und Alkylenedioxy-arylaminopropanen bzw. deren Amstickstoff Monoalkylierten Derivaten. German Patent, No. 274 350, 1914.
A.T. Shulgin, The background and chemistry of MDMA. J. Psychoactive Drugs, 18 (1986) 291–304.
G.N. Hayner and H. McKinnon, MDMA. The dark side of Ecstasy. J. Psychoactive Drugs, 18 (1986) 341–347.
A.M.A. Verweij, Clandestine manufacture of 3,4-methylenedioxy-methylamphetamine (MDMA) by low pressure reductive amination. A mass spectrometric study of some reaction mixtures. Forensic Sci. Int., 45 (1990) 91–96.
F.T. Noggle, C.R. Clark and J. DeRuiter, Gas chromatographic and mass spectrometric analysis of samples from a clandestine laboratory involved in the synthesis of Ecstasy from Sassafras oil. J. Chromatogr. Sci., 29 (1991) 168–173.
T. Lukaszeweski, Spectroscopic and chromatographic identification of precursors, intermediates and impurities of 3,4-methylenedioxyamphetamine synthesis. J. Assoc. Off. Anal. Chem., 61, 951–967 (1978).
M.L. Moore, The Leuckart reaction. Organic Reactions, 5 (1949) 301–330.
E. Merck, Verfahren zur Gewinnung von Formylderivaten sekundarer Basen. German Patent 334,555 (1920)
K. Bailey, A.W. By, D. Legault and D. Verner, Identification of the N-methylated analogs of the hallucinogenic amphetamines and some isomers. J. Assoc. Off. Anal. Chem., 58 (1975) 62–69.
A.M. van der Ark, A.M.A. Verweij and A. Sinnema, Weakly basic impurities in illicit amphetamine. J. Forensic Sci., 23 (1978) 693–700.
A.M.A. Verweij, Impurities in illicit drug preparations: amphetamine and methamphetamine. Forensic Sci. Rev., 1 (1989) 1–14.
T.C. Kram and A.V. Kruegel, The identification of impurities in illicit methamphetamine exhibits by gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy. J. Forensic Sci., 22 (1977) 40-52.
T.A. Dal Cason, The characterization of some 3,4-methylenedioxyphenylisopropylamine (MDA) analogs. J. Forensic Sci., 34 (1989) 928–961.
F.T. Noggle, C.R. Clark, A.K. Valaer and J. DeRuiter, Liquid chromatographic and mass spectral analysis of N-substituted analogues of 3,4-methylenedioxyamphetamines. J. Chromatogr. Sci., 26 (1988) 410–415.
A.M. van der Ark, A.B.E. Theeuwen and A.M.A. Verweij, Impurities in illicit amphetamine; isolation and identification of some pyrimidines. Pharm. Weekbl., 112 (1977) 977–982.
J.V. Jackson and A.J. Clatworthy, Toxicological applications of chromatography. In I. Smith and J.W.T. Seakins (eds.), Chromatography and Electrophoretic Techniques, Vol. 1, Paper and Thin Layer Chromatography, William Heinemann Medical Books Ltd, 1976, pp. 380–455.

Impurities in Commercially Available MDP2P

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Introduction

Diketone compounds are known impurities present in the ketones that are used as starting materials in the different syntheses of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA)¹. No further studies have been reported in the literature on impurities present in piperonylmethylketone (PMK) (also known as 3,4-methylenedioxyphenyl-2-propanone, MDP2P), used in the illicit production of MDA. Some of these impurities, and their structures, have been determined in commercially available PMK.

Experimental

Analyses were done on a 1:40 dilution of PMK with chloroform. Gas chromatographic-mass spectral analyses were performed on 1 uL injections using a HP 5971A MSD interfaced with a HP 5890 GC. The MSD was operated in the EI mode. The samples were introduced into the GC via a split injector equipped with a 12.5 m x 0.2 mm id HP Ultra-1 fused silica capillary column with a 0.33 um film thickness. The column temperature was programmed from 100 to 280°C at a rate of 10°C per minute. The injection port was 275°C and the transfer line temperature was 280°C. He was used as the carrier gas with a flow rate of about 1 mL/minute.

Results and discussion

Table 1

Peak	Compound Name	MW.	Formula
A	Safrole	162	C₁₀H₁₀O₂
A	Isosafrole	162	C₁₀H₁₀O₂
B	Piperonal	150	C₈H₆O₃
C	4-Allyl-1,2-dimethoxybenzene	178	C₁₁H₁₄O₂
D	Piperonylmethylketone (PMK, MDP2P - Main Component)	178	C₁₀H₁₀O₃
E	3,4-Methylenedioxyphenyl- 2-propanone-(3-ol)	194	C₁₀H₁₀O₄
F	3,4-Methylenedioxyphenyl- 1-propanone	178	C₁₀H₁₀O₃
G	3,4-Methylenedioxyphenyl- 1-butanone	172 (sic)	C₁₁H₁₂O₃
H	4-Isopropyl-1,6-dimethyl- 1,2,3,4-tetrahydronaphtalene	202	C₁₅H₂₂
I	3,4-Methylenedioxyphenyl- propionic acid-2-one	208	C₁₀H₈O₅

The total ion chromatogram (TIC) of a solution of PMK in chloroform is shown in Fig 1 (not included). From the abundance values for the peaks in the TIC shown in Fig 1, the purity of the PMK was estimated to be greater than 95 percent. In the same way, the impurities were found to range from about 0.1 to 1.0 percent. The structure elucidation of the different compounds in the TIC was done by comparing the mass spectral data with different databases^1-3 and applying known fragmentation rules^4,5. In Table 1, the proposed structures of the impurities together with the mass spectral data are given. All the detected impurities except compounds C and H, have the methylenedioxy group, whereas the other structural differences of the impurities are in the substituents attached to the other side chain of the phenyl group. A trace quantity of safrole, as well as isosafrole, was found, giving rise to the assumption that at least the oxidation of safrole in formic acid by hydrogen peroxide was part of the process of manufacturing PMK. The presence of the oxidation products of PMK, the alcohol and the acid (compounds E and I in Table 1), also points to an oxidative process.

References

AMA Verweij. Impurities in illicit drugs preparations: 3,4-(methylenedioxy)amphetamine and 3,4-(methylenedioxy)methamphetamine. Forensic Science Review 4, 138-146 (1992)
Eight Peak Index of Mass Spectra, The Mass Spectra Data Center, The Royal Society of Chemistry. 1983
FW McLafferty, DB Stauffer. The Wiley/NBS Registry of Mass Spectral Data. John Wiley and Sons. 1989
JR Chapman. Practical Organic Mass Spectrometry. John Wiley and Sons. 1985
FW McLafferty, Interpretation of Mass Spectra, University Science Books. 1980

MDP2P by 2-Nitropropene Alkylation of 1,3-Benzodioxole

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To a 3-necked 500 ml flask under a nitrogen atmosphere was added 300 mL of dry DCM, 0.1 mole of 2-Nitropropene (8.7g) and 0.5 moles of 1,3-Benzodioxole (61 g). The flask was then secured within a dewar flask sitting on top of a magnetic stirplate. Dry ice was added to the dewar flask which was filled with acetone until a temperature of approx -78ºC was acquired. Once the internal flask temperature of -70ºC was reached, 0.1 mole (19 g) of TiCl₄ was dripped slowly into the stirred solution. The temp started to rise so the addition was controlled to keep the internal flask temp around -60°C to -70ºC. The flask was then stirred for 30 mins at -70ºC, by which time the precipitate which formed from the addition had dissipated. The dewar flask was removed and the stirring solution was allowed to warm up to room temperature, during which time the black solution will change viscosity and colour.
To hydrolyze the formed nitro-titanium complex, 100 mls of water was added to the solution which was then refluxed for 2 hours. During the reflux a brown gas (probably NO₂) is evolved. The flask was cooled and vacuum filtered (cleans it up a lot) the water layer seperated and discarded. The organic layer was then washed with 3x200 mL of 10% NaOH and 1x200 mL of a brine solution. It was then dried with magnesium sulfate, the DCM evaporated and resulting orange-yellow oil vacuum distilled. The 1,3-Benzodioxole came over at 40-45ºC at 10 mbar then a yellow-green fluorescent oil (MDP2P) began distilling at 135ºC at 3 mbar.

8 grams of MDP2P was collected, corresponding to 45% yield from 2-Nitropropene or 23.5% from 1,3-Benzodioxole (calculated on the amount of 1,3-Benzodioxole not recovered during workup).
Reference: Tetrahedron Letters, Vol 29, No 24, pp. 2977-2978 (1988)

Pseudonitrosite FAQ

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Related info: Pseudonitrosite Synthesis, as Performed by Pugsley

Introduction

The hitherto pretty unknown pseudonitrosites are nitrogenous compounds which are formed by the action of N₂O₃ (an equimolar mixture of NO and NO₂) upon etheral solutions of some unsaturated compounds, for example propenylbenzenes and styrenes. They were popular in the late 1800s and early 1900s, but has since then been forgotten(?). After around WWII, there is not a single mention of them in the literature, not even in such a reference work on the subject as Nitroalkenes - Conjugated Nitro Compounds¹.
The pseudonitrosites were discovered by Toennies around 1880, when he made the pseudonitrosite of anethol, but he failed to recognize the constitution of the compound, and mistakenly assigned it the structure of a vicinal ketoxime/nitrite. In the early 1890s, the Italian chemist Angelo Angeli experimented with different allyl- and propenylbenzenes, and again encountered the pseudonitrosites, but he couldn't either determine their exact structure, and with the methods used in analytical chemistry back then, this is understandable. In the early 1900s, the puzzle was solved by studies on styrene pseudonitrosite, and around this time Wallach and Wieland published reviews of pseudonitrosite chemistry^2-3. Very little about pseudonitrosites can be found in Chemical Abstracts, so most pointers to earlier work must be retrieved from the references cited in those articles.
In the 1930's, Victor Bruckner began to explore the possibility of using pseudonitrosites as an intermediate in the synthesis of substituted 1-phenyl-2-amino-propanols, and in his articles he also included improved syntheses of several pseudonitrosites from propenylbenzenes, as well as studies on the pseudonitrosites themselves. One of the most useful reactions he investigated was the basic hydrolysis of propenylbenzene pseudonitrosites, yielding the corresponding beta-nitro derivatives of the propenylbenzenes. This route offered several advantages over the known nitration of alkenes with tetranitromethane, which is expensive, toxic and explosive. In his papers on pseudonitrosites, Bruckner described several experiments with asarone⁴, methylisoeugenol and isosafrole⁵, isoeugenol⁶ and anethole⁷. In the experimental part below, some freely translated parts of his work is included.

Fig 1. Formation of Asarone Pseudonitrosite

Theory

Several methods for the synthesis of pseudonitrosites have been used, such as bubbling N₂O₃ through a solution of the propenylbenzenes in ether, slow addition of a NaNO₂ solution to a solution of the propenylbenzene in glacial acetic acid (Toennies' method), as well as dripping a dilute solution of sulfuric acid into a two-phase solution of NaNO₂ in water and a propenylbenzene in ether (Bruckner's method).

Fig 2. N₂O₃ from NaNO₂ and H₂SO₄

The action of a strong acid (such as sulfuric acid) on sodium nitrite gives the sodium salt of the strong acid, as well as free nitrous acid (HNO₂), which in turn breaks down to an equimolar mixture of NO and NO₂ gas (see Fig. 2). This gas mixture is in equilibrium with dinitrogen trioxide: N₂O₃ ←→ NO + NO₂
At 25°C and normal pressure, only about 10% of the gas is in the form of N₂O₃, and the equilibrium mixture behaves just like as if it was a mixture of NO and NO₂. But, for the sake of simplicity, the equilibrium mixture is commonly called N₂O₃, or dinitrogen trioxide.

Fig 3. N₂O₃ from HNO₃ and iron

N₂O₃ can also be formed by the action of nitric acid (which in turn can be made by dissolving NaNO₃ or KNO₃ in conc H₂SO₄) on certain metals, for example iron (see Fig. 3). The more finely divided the metal, the faster generation of gas. But there is a downside to this method. In the beginning the nitric acid is concentrated, but as N₂O₃ is evolved, the solution becomes more and more dilute. There is a problem associated with this, the ratio of NO to NO₂ isn't constant if the concentration of the acid changes. Concentrated acid gives excess NO₂, and a dilute acid solution gives excess NO. To get maximum yields out of the treated propenylbenzene, the proportions between NO and NO₂ should always be as close to 1:1 as possible, and only the sodium nitrite method will constantly produce a gas mixture with just those proportions. Producing dinitrogen trioxide with the nitrate method is therefore discouraged. This method does not work at all with asarone (only with other propenylbenzenes, such as isosafrole or anethole) according to Bruckner⁴.

Fig 4. Dimerization of Asarone Pseudonitrosite

The pseudonitrosites always dimerizes to the bis-pseudonitrosites, all of which are practically insoluble in water, alcohols and most common organic solvents, with the exception of warm chloroform or ethyl acetate, in which a blue-green solution is produced, consisting of the dissociated pseudonitrosite monomer. During the treatment of a propenylbenzene with N₂O₃, the intensely colored free monomer can be observed for a while before it dimerizes to its crystalline form. The colors of the crystalline pseudonitrosites varies, from the snow-white isosafrole or anethole derivatives to the canary-yellow one obtained from asarone. Upon storage, pseudonitrosites soon decompose with discoloration, releasing nitrogen oxides and hydrogen cyanide. At around 40°C decomposition takes place in less than one day.

Fig 5. Hydrolysis of Asarone Pseudonitrosite Dimer

Treatment of the pseudonitrosite dimer with four moles of an inorganic base (such as KOH in alcohol), produces two moles of potassium hyponitrite (K₂N₂O₂) and two moles of the water-soluble potassium salt of the corresponding nitroalkene. Acidification of the potassium salt solution with dilute acid precipitates the water-insoluble phenyl-2-nitropropene as fine crystals, and the liberated hyponitrous acid breaks down into water and nitrous oxide (N₂O), which can be observed as fine bubbles that is being evolved during this step.
The reaction of a pseudonitrosite with acetic anhydride produces the alpha-acetoxy derivative with release of N₂O, and after reduction of the nitro group this could be hydrolyzed to ring substituted phenylpropanolamine derivatives. Basic hydrolysis of the alpha-acetoxy derivative also produces the phenyl-2-nitropropene. Reaction of pseudonitrosites with primary amines yields secondary alpha-amino derivatives.

Experimental

All these procedures are presented for informational purposes only. These procedures should not be carried out without adequate precautions taken. In most of the procedures highly toxic fumes of nitrogen oxides can evolve, which are irritating on mucous membranes and can destroy lung tissue. Use only with good ventilation. The author assumes no responsibility for any damage or legal consequences resulting from misuse of this information.

Pseudonitrosites^4,5,7

A solution of 1 mole (69 grams) of sodium nitrite in 100 ml water was prepared in a 500 ml flask, and a solution of 0.1 moles of a freshly distilled propenylbenzene (20.8g asarone, 16.2g isosafrole or 14.8g anethole) in 150 ml of diethyl ether was added. During a period of 3-4 hours, a 20% solution of H₂SO₄ (prepared by cautiously adding 0.5 moles (49 grams) of conc. sulfuric acid to 200 ml of H₂O) was added dropwise with magnetic stirring, preferably through a pressure- equalized addition funnel. Watch the addition rate so that the temperature of the two-phase solution doesn't rise over room temp, and this solution can preferably be cooled during the addition In the beginning of the addition of acid, monomeric pseudonitrosite can be seen in the etheral layer. The monomer derived from asarone is greenish, anethol blueish and isosafrole yellow. If oxygen gets into the system during the addition, formed NO oxidizes to brown NO₂ gas, which can lower the yield of pseudonitrosite. After the addition, the solution was allowed to stir for an hour or two, whereafter the solution was filtered with suction, and the precipitate washed with 50ml each of water, denatured alcohol and finally ether. After sucked as dry as possible, the pseudonitrosite crystals was allowed to air dry on a filter paper.

Pseudonitrosite	Color	Yield	Melting point
Asarone	Yellow	16.5g, 58% (22.8g/80%)⁴	130°C(dec)⁴
Isosafrole	White	77% (18.4g)⁵	128°C³
Anethole	White	48% (10.8g)⁷	126°C(dec)⁷

Pseudonitrosites cannot be stored, as they begin to decompose within hours at room temperature with the evolution of nitrogen oxides, and should be further processed to for example the very useful phenyl-2-nitropropenes, which upon reduction can yield phenylacetones and amphetamine derivatives.

Phenyl-2-nitropropenes^4,5,7

0.1 mole of the corresponding propenylbenzene pseudonitrosites (28.5g asarone, 23.8g isosafrole or 22.4g anethole) was dissolved in 150ml 8% alcoholic KOH with shaking, and possibly light heating (not over 30°C, especially not in the case of asarone pseudonitrosite, or there is a risk of decomposition (to the aldehyde, amongst other things). Caution: Foaming with evolution of N₂O will occur. The cloudy solution was suction filtered, and the filtrate was poured onto 100 grams of crushed ice. The solution was acidified with dilute HCl and was stirred occasionally until the ice had melted. The precipitate of nitropropene was filtered off, washed with a little cold water and air dried.

Nitropropene	Color	Yield	Melting point
Asarone	Yellow/red^*	19.7g, 78%	101°C⁴
Isosafrole	Yellow		98°C⁵
Anethole	Yellow		47°C⁷

*) 2-Nitroasarone exists in two modifications, yellow or red prisms, and depending on concentration and precipitation speed, one often gets a mixture of both species. They both melt at 101°C, the red form transforming itself to the yellow form at 90°C.

References

V. V. Perekalin, E. S. Lipina, V. M. Berestovitskaya, D. A. Erefmov, Nitroalkenes (Wiley, 1994)
H. Wieland, Zur Kenntniss der Pseudonitrosite, Ann. 329, 225-268 (1903)
O. Wallach, Ueber die Additionsproducte von N₂O₃ und von NOCl, Ann. 332, 305-336 (1904)
V. Bruckner, Ueber das Pseudonitrosit des Asarons, J. Prakt. Chem., 138, 268-274 (1933)
V. Bruckner, Ueber die Verwendung der Pseudo-nitrosite , Ann. 518, 226-244 (1935)
V. Bruckner, Ueber die Verwendung der Pseudo-nitrosite II, J. Prakt. Chem. 143, 287-297 (1935)
V. Bruckner, Ueber die Verwendung der Pseudo-nitrosite III, J. Prakt. Chem. 148, 117-125 (1937)

Photoamination - One step from isosafrole to MDMA

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Photoamination of Methylstyrenes

The Possible One-pot-shot From Isosafrole to MDMA

by Drone #342

By far, one of the most fascinating possible methods of making MDMA is the insanely elegant photolytic reaction between isosafrole and methylamine. For years, like many other individuals, I looked at isosafrole and methylamine and dreamed that somewhere there was a method of adding the two together in a single step, rather than having to make MDP-2-P, then reductively aminate it, and go through all the tedious steps involved. As it turns out, such a method exists: photo-induced nucleophilic amination.
The general idea is this: an alkoxy-substituted methylstyrenes (in this case, isosafrole), p-dicyanobenzne (DCB), methylamine, and triphenylbenzne (TPB), are disolved in acetonitrile, exposed to light, and the reaction occurs. Here's the mechanism:
p-DCB absorbs a photon, gets activated, and abstracts an electron from isosafrole's double bond, leaving the carbon beta to the benzene ring (in the 2-position) positively charged. From there, the nucleophile (in this case methylamine) attacks the aforementioned carbon, and releases a hydrogen. The hydrogen is then scooped up by the cationicly-charge alpha carbon.
The basis of this technology is some research done in 1973, involving the addition of MeOH across double bonds. During the early 90's, some Japanese researchers had the ingenuity to apply this to ammonia as a nucleophile, then tried alkylamines as well. Both were greatly successful, and were directly applied to the synthesis of phenethylamines. Fortunately for MDMA enthusiaists, several papers of theirs focused on the synthesis of methoxylated aryl isopropylamines -- which is exactly what MDMA is. Though MDMA was never expressly synthesized by these fellows, one can easily apply the techniques they developed to MDMA production.

General method for the production of amphetamines from methyl styrenes, lifted from the literature.

"General procedure of Photoamination. Into a Pyrex vessel was introduced an MeCN-H2O (9:1, 70 mL) solution containing 1-4, 6-8 [various styrenes] (3.5 mmol) and DCB (3.5 mmol), and then the solution was bubbled with gaseous ammonia. The solution was irradiated by an eikosha PIH-300 high pressure mercury vapor lamp under cooling with water. The progress of the reaction was followed by GLC analysis..."

Proposed experimental method.

Proposed procedure of photomethylamination of isosafrole. Into a Pyrex vessel was introduced an MeCN-H2O (9:1, 70 mL) solution containing isosafrole (C10H10O2; 0.567 grams, 3.5 mmol) and DCB (3.5 mmol). The solution was then saturated with methylamine gas. The solution was irradiated by a 300-W high pressure mercury vapor lamp under cooling with water. Upon completion, the solvent was stripped in vacuo, and the residue was washed an aqueous 10% NaOH solution, and extracted with DCM. The DCM was stripped in vacuo, and the oil distilled in vacuo, yielding the free base of MDMA. The base was disolved in dry Et2O, and dry HCl gas was bubbled in. The precipitated crystals then dried, weighed, and tested for biological activity.

By definition, this is an oxidative amination. For old MDMA chemhacks, familiar with reductive amination, this should sound a little weird, but hey, it works.

Bibliography: a reading list of the good stuff

Neunteufel, R. A., Journal of the American Chemical Society, 1973, 95, 4080-4081

This is the original study of photo-induced nucleophilic addition that inspired the later use of ammonia. While its only marginally useful, it's a good place to start to understand some of the theory of this process.

Tetrahedron Letters, 1993, 34, 5131-5134

This is a quick, general sneak-preview of the later study of phenethylamine synthesis. Nice, basic, but not too much detail

Tetrahedron, 1994, vol. 50, no. 31, 9275-9286

"Photoinduced Nucleophilic Addition of Ammonia and Alkylamines to methoxy-Substituted Styrene Derivatives" This is the Mack-daddy of all the articles, IMHO. Here's where they show what they got, and lay out the procedure and conditions that would be used for making MDMA.

Bulletin of the Chemical Society of Japan, 1998, vol 71, no 7, 1655-1660

"Photoamination of Alkenylnaphthalenes with Ammonia via Electron Transfer" A further study, where aryl isopropylamines are made from their corresponding alkenes. This one's good for several reasons: the use of methylamine, and the evidense it has proving the usefulness of both isomers of isosafrole. The Tetrahedron article by the same research group before used only the trans isomer, but not the cis.

Links to other selected photochemistry (and otherwise related) web pages.

US Pat #4,483,757:Photochemical process for preparing amines
US Pat #4,459,191: Light-catalyzed process for preparing amines

MDMA via Tosyl Chloride Intermediate?

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Ollie-RSM

Has anyone ever heard of MDMA being produced by a Markonikov hydration of safrole and conversion of the alcohol to an alkyl tosylsulfonate (via rx with tosyl chloride) followed by S_N2 amination with methylamine? This synthetic pathway would be very similar to the bromination/debromination pathway that is recently in vogue, and might be even simpler. Plus tosyl chloride is dirt cheap ($23 for 1kg).

Siegfried

I try this procedure alot and it was much better than normal alkyl-halide process because the tosylate (and brosylate or nosylate) don't give a lot of elimnation contrary to the alkyl-halide. I got the alkohol intermediate with oxymercuration of the allylbenzene and made the tosyaltion with tosylchloride/pyridine, then the SN2 in MeOH with a little THF for solubility purpose and RT . The yield and reaction time are:

>95%, 20min, RT for oxymercuration
>95%, 45min, RT for tosylation
50-60%, 5d, RT for S_N2 with MeNH₂-MeOH

The RT and polar solvent are very important because increase the temperatur favorise the elimination, decrease the polarity too. Anyway, this family of S_N2 is favorised with polar protic solvent as MeOH (see the March). As I wrote under another topic, the tosylate are very good but there is even better leaving group they don't give any elimination and have better kinetics: the Triflate, but it's an expensive reagent.

For the tosylation of alkohol, the base is pyridine, because

It neutralizes the HCl
It form a complex with tosyl chloride which significantly facilitates the attack by the alcohol on the sulfur

For the hydratation of the alkene, acid medium is not good because the 1-aryl-2 propanol first formed is rapidly deshydrated to the stabilized isosafrole wich is hydrated to the 1-aryl-1-propanol. The result is:

Very poor yield in 1-aryl-2-propanol
Mixture of 1-aryl-2-propanol and 1-aryl-2-propanol which are not easy to separate (must use distillation).

The oxymercuration process give only the 1-aryl-2-propanol intermediate without rearrangement in about 20min with >95% yield but HgCl₂ can not be used, sorry. Hg(OAc)₂ or Hg(NO₃)₂ or Hg(ClO₄)₂ or Hg(CF₃COO)₂ can be used. You must use Hg²⁺ (mercuric) and not Hg⁺ ion (mercurous). You can make Hg(OAc)₂ from HgCl₂ + CH₃COOH but you must purify it. Anyway Hg(OAc)₂ can easily be purchased.

Tr-E-frog

Thank you for the informative post. What originally got me interested in this method was the fortuitous discovery of 'triflate' anhydride in reasonable quantity. Have you used this leaving group in this reaction? Would you mind posting the details of your procedure? Ultimately, I suspect that the cost of this reagent makes it impractical for any scale up but for a small scale high-yield experiment it may be interesting.

Ritter

I believe the only better leaving group than tosyl is methanesulphonate from mesyl chloride, of course. The methanesulphonly group will probably provide yields 10% or so better in S_N2 substitution w/ anhydrous alcoholic methylamine or ethylamine soln. Methanesulphonyl chloride is a little more expensive than tosyl chloride however it is a liquid and therefor much simpler to handle than stinky irritating tosyl chloride.
On a side note safrol-2 mesylate reacted in 80% yield with excess benzylamine to make N-benzyl MDA which was easily hydrogenated at 30 lbs w/ five percent loading of 10%Pd/C catalyst to produce a total yield of 73% MDA from starting alkene. not too shabby! The methylenedioxyphenyl-2-propanol was generated from methylenedioxyphenylacetaldehyde w/ MeMgI grignard.

Siegfried

Ritter: the oxymercuration process is very simple and easy to carry : RT , >95% yield , 25min reaction time ... The mesylate group is about the same than tosylate or nosylate or brosylate but the best known leaving group are triflate and nonaflate , tresylate is not so good it's about 400 time less reactiv than triflate but it is still about 100 time more reactiv than tosylate and analogs ... Conclusion : triflate is 4000 time more reactiv than tosylate and analogs ( mesylate , brosylate , nosylate ) . For a good explanation of the leaving goup see the chemist bible : "Advanced organic chemistry - Jerry March " chapter : nucleophilic substitution.

Siegfried

The tosylation must be conducted in pure pyridine. 11 mmole tosylchlorid is added slowly ( t<30°C ) to a stirred solution of 10 mmole alkohol in 10 ml pyridine. When tosyl chloride is added, the mixture is stirred for 30-40 min RT. Then the mixture is poured in 100ml 2N HCl, then tosyl is purified . Yield over 95%.

Ritter

Just dug up some references for advancement of tosylate/mesylate esters as feasible, HIGH YIELDING synthetic intermediates to our beloved honey in an aqueous environment.

The following is quoted from: Journal of Organic Chemistry 53, 4081-4 (1988)
(R)-Tomoxetine Hydrochloride: A solution of phenyl-3-(2-methylphenoxy)-propyl methane sulfonate [the mesylate group is on the gamma carbon] (450mg, 1.45mmol) and methylamine (10ml, 40% in water) in THF (10ml) was heated to 65'C for 3h. After cooling, the solution was diluted with ether, washed w/ aq. sat. NaHCO₃ soln. and brine, and dried with anhydrous K₂CO₃. After concentration a pale yellow oil was obtained which was dissolved in ether, bubbled w/ dry HCl gas [and you guys certainly know the rest] to produce a white ppt which was recrystallized w/ acetonitrile to yield title compound (400mg, 94%)

Thats amazing! NINETY FOUR freakin percent from an aqueous MeAmine soln!!! Try achieving that with a halogen leaving group on our favorite alkene by cooking the stinky shit up in a pipe bomb w/ alcoholic MeAmine. You can't, if you are lucky 50% will be . Halogens blow as leaving groups compared to sulfonate derivatives as proved by this paper. It is such an advantage to be able to use good 'ol fashioned aqueous MeAmine compared to homebrew anhydrous alcoholic amine solns! The only drawback noticed immediately is the large excess of MeAmine employed by the authors. This shouldn't present a huge problem because the excess amine cooked off during the heating process can be collected by bubbling through HCl. The 65°C rctn temp is the bp of THF so excess amine will be liberated out of the top of the reflux condensor on rctn pot. A slow stream of N2 can be admitted through a bubbler in the second neck of the rctn. flask forcing the methylamine gas to be expelled out the top of the condenser into a beaker of HCl. Simply evap off HCl to obtain your excess amine back as MeAmine hydrochloride.
There is one other procedure for producing alkyl-methylamines from an alkyl mesylate using the exact same protocol listed above with product isolated in 96% yield! This proves the procedures high yields are reproducible, however both examples listed are performed on primary alkyl mesylates. Since we are working with a secondary alkyl mesylate yields may suffer a bit from steric hindrance during the nucleophilic substitution by MeAmine. Well actually, let me restate that.. my chem theory is getting a little weak.. In most if not all nucleophilic substition reactions in the literature compounds with a leaving group always have higher yields in nucleophilic substition rctns than a complementary compnd w/ a secondary leaving group. Therefore the mesylate in our case may not produce the 90+% yields quoted in the literature but it sure will be much higher than that produced by any halogen.
Siegfried: Excellent work in this area. Was wondering if you'd be kind enough to post the physical properties of the tosylate. Simple experience has proved that most tosylates are solids, however you're the only one who knows for sure. A melting pt. would be very useful. Any recrystallization solvent of choice?
Was an attempt ever made at esterifying the propanol produced w/ H₂SO₄? As a side note any tertiary amine can be used in a similar manner as pyridine to scavenge protons in the esterification rctn. Triethylamine was the amine of choice in the quoted article. Yields of 85% were recognized after several wasteful recrystallizations.
On the subject of hydration of alkene to alcohol, oxymercuration is obviously the most simple method considering rctn. time and yield. However soluble mercury salts just plain suck. It sure would be nice if the H₂SO₄ thing worked. Another possible synthesis may be a PTC rctn. between aq. NaOH and halosafrole. This is a well documented rctn. however conditions will probably have to be closely monitored to minimize isoalkene formation.
Finally, to sum everything up this is a major breakthrough because of the reactivity of amines to sulfonic esters in aqueous environment. Similar reactions in the past have usually reacted alkyl halides as leaving groups and fickle-to-make alcoholic amine solns with long rctn times or high temperature pipebomb pressure vessels. Not very desirable when compared w/ a 3hr STP reflux. Reported yields are also very poor w/ halide exchange rctns. Comment?

MDA from Bromosafrole using PTC and an azide

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Procedure¹

A mixture of 2-bromosafrole (24.1g, 0.1mol), hexadecyltributylphosphonium bromide (5.1g, 0.01mol), sodium azide (16.2g, 0.25mol), and water (50ml) is magnetically stirred at 80°C for 24 hours. Flask is cooled and phases are separated in sep funnel. The dark reddish organic layer is diluted with toluene (20ml) and poured back into flask and stirring is restarted. A solution of sodium borohydride (11.7g, 0.3mol) in water (30ml) is carefully added through an addition funnel over 30 minutes as temp is raised to 80°C and held there for 16h. Contents of flask are cooled and poured into a sep funnel. Aqueous layer is sepped off and organics are washed with 50ml dH₂O. Three 40ml portions of 4M HCl (approx 10%) are used to extract MDA base from organic layer. Combine all acid extracts and neutralize with 50% NaOH soln. Golden beads of MDA base will fall out of soln. Use two portions of 50ml toluene to isolate base. At this point one of two things can be done. If you are a greedy shoddy chemist you will dry the toluene extracts with anhydrous MgSO₄ then bubble with HCl gas to isolate a relatively pure white MDA hydrochloride (8-12g) OR if you have any pride in your chemistry skills and product, toluene will be evaporated down to a orange oil and vacuum distilled using standard methods to yield 6.5-11.0g of water white pristine MDA base. Distilled base is most easily crystallized by adding about 6 times volume of dry IPA and neutralizing w/ conc. HCl. Place this in the freezer over night to find glorious white crystals of the hydrochloride. At this point not all of the salt has precipitated and it won't no matter how long you leave it in the freezer, so add the same volume of dry acetone to ppt. entire yield (6-12g, or 27-56% yield from bromosafrole).

Notes:

2-Bromosafrole was prepared using process developed by Fester. HCl(g) is bubbled into a soln of 48%(aq)HBr, HOAc and PURE DISTILLED safrole. The procedure is archived on Rhodiums site and runs exactly as Fester claims, believe it or not!
Yield of product is totally dependant on reaction time/temp of first step. If literature citing is examined yields above 85% are reported for all primary alkyl bromides. Problem with lower yield here is the fact that we are dealing with a secondary bromide. This introduces the possibility of occurrence of two yield killing side reactions. Elimination of -Br resulting in isosafrole then elemination of azide may occur resulting in more isosafrole. Perhaps reducing the temp and extending rxn time will slow rate of elimination resulting in higher yield of alkylazide. Someone willing to try?
Chlorosafrole does not work satisfactorily at all in this procedure. If you want to use that as a starting material, first perform a Finkelstein swap with NaI in acetone to form Iodosafrole, which is as reactive as Bromosafrole using this method.
The PTC suggested in the original reference¹ (hexadecyltributylphosphonium bromide) is very expensive. Substituting an equimolar amount of Aliquat 336 (3.4g, 0.01 mol) in the procedure above is a cheaper alternative, and gives comparable results.

Synthesis of MDE from 2-Azidosafrole

by Foxy2
Instead of extracting the azide with toluene use xylene. Use a well dried xylene extract in the following procedure.

Example using cyclopentyl azide²

In a dry 50ml flask equiped with septum inlet, reflux condenser, and magnetic stirrer was flushed with nitrogen. The flask was charged with 10mL xylene and 0.98g, 1.42ml (10 mmol) of triethylborane. The solution was then heated to reflux and attached to a gas buret. Then 1.11g (10 mmol) cyclopentyl azide was added. After completion of nitrogen evolution, the flask was cooled, 30 ml diethyl ether was added and the amine extracted with 6 M HCl, two 20 ml portions. The aqueous phase was then washed with ether to remove residual borinic acid. Yield 77%.

Synthesis of MDMA from 2-Azidosafrole

by Ritter
This reference is a significant advance in alkylazide reduction techniques because it reduces the azide and methylates it in one single step. This is the only ref I am aware of which yields a N-methylamine directly from the azide precursor without using catalytic hydrogenation for the reduction.

Sample procedure³

Secondary alkylazide (0.148mmol) in CH₂Cl₂ (1.5ml) was added a solution of (CH₃)₃P in toluene (1.0M, 0.3mL) at room temp. After stirring for 1.5hr, paraformaldehyde (22.6mg, 0.753mmol) was added. The rxn. mixture was stirred for an additional 6hr at room temp then rxn was cooled to 0°C and MeOH (2.0ml) and NaBH₄ (28mg, 0.74mmol) was added. After stirring for 30 min the rxn. was quenched with saturated aq. NaHCO₃ and extracted with 5×10ml CH₂Cl₂. Extracts were pooled and evaporate to yield 83% N-methylamine.

References

J. Org. Chem., 47, 4327
The reaction of organic azides with triethylborane. A new route to secondary amines. J. Am. Chem. Soc. 93, 4329-4330 (1971)
Convenient Procedure for One-pot Conversion of Azides to N-monomethylamine, Synlett 1003-1005 (2001)

Complete MDMA Synthesis by Dr Drool

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MDMA Synthesis Story

What follows is, of course, a work of pure fiction. In it, I have tried to illustrate something of the mental state of an individual whose mind was severely altered when he took his first dose of ecstasy and decided that he would love to take more. Doctor Drool, the protagonist, was paranoid about taking street drugs, but was quite confident of his own abilities in a chemistry lab, although he had not exercised those abilities for 20 years. He was moderately well trained in chemistry in the university (two full years of inorganic and organic classes with labs), but he had not done or even thought about lab work for many years.
The manufacture of ecstasy is, of course, totally illegal and degenerate, and the author feels that anyone who tries to do it should be hauled in front of John Ashcroft's military tribunals and then executed (or executed first; it doesn't really matter).
Although in the story that follows, the protagonist has so far avoided arrest and execution, I'm certain that he will receive the punishment he deserves any day now.
Any relationship between the methods described by Doctor Drool and reality are, of course, completely coincidental, but to make the story more believable, I have included text from actual web pages, perhaps written by real degenerates, not like the fictional Doctor Drool.
I hope you enjoy the story. If it keeps just one person from falling into the hell of ecstasy (or, as the addicts sometimes call it, "rolling" on MDMA, ADAM, E, X, or XTC), it will have been worth the effort of writing.
-- the author, Feb 25, 2002

Introduction:

I initially tried to follow the BrightStar synthesis that I found on the internet but the only part that was reasonable was for the distillation of safrole from the raw sassafras oil. It was, however, good to read BrightStar's description just to remind myself about some chemistry techniques that I hadn't done for 20 years. I later found other syntheses on the internet for all the steps between legal chemicals and MDMA that worked quite well.
At least at the current time (early 2002), all the chemicals and apparatus mentioned here are available legally. Aside from the ecstasy, of course, the only other intermediate products that you will produce along the way that are at the least highly suspicious are the pure, distilled safrole and the ketone MDP-2-P. The unfortunate thing about the ketone is that although you probably have a million good places to hide the ecstasy and the safrole, the MDP-2-P must be kept in the freezer. The folks from the DEA know this. Luckily, the ketone is only necessary for the final synthesis, so I made it just before I needed it, and then repeated the final step until the ketone was all used up. Now when the DEA breaks down my door, they've got to find less than an ounce of white powder (maybe I should label it "anthrax") in an unknown form rather than find a little jar of antifreeze-colored green fluid in my freezer.
Make certain that you have (or know you can obtain) all of the stuff (chemicals and apparatus) before you begin. For example, at the time BrightStar wrote his synthesis, it may have been easy to obtain dimethylformamide; now, it is not. If you decide to embark upon this project, it is not going to be cheap, assuming you're starting from scratch. I spent perhaps $1100 total -- $800 for lab supplies (glassware, hotplate-stirrer, clamps, stands, vacuum pumps, et cetera), and $300 for chemicals. If I decide to do it again, it'll probably cost me another $200 (and I'll get a lot more product the second time).
My overall impression is that the synthesis is moderately difficult, at least for someone who last took an organic chemistry lab course more than 20 years ago. I was quite good in the labs back then, and also understood the chemistry quite well. I took the time to understand to a pretty good degree the chemistry in this synthesis. The more anal-compulsive you are, the better you'll do. Study the reactions. Understand how they work. Although it would seem that you could just follow a cookbook method, it's amazing how much better that works when you know exactly what you are doing and why you are doing it.
If I had tried this synthesis without experience with organic chemistry laboratory techniques, I have severe doubts that I'd have been able to pull it off. If you are without experience but would still like to try, remember that most junior colleges offer lab courses in organic chemistry. Take one of those and concentrate on getting an A+ in the lab part.

Overall notes:

(This stuff is in no particular order -- there may be more important stuff following less important stuff.)
This process is going to take a long time. Even if you had all the stuff you needed, it takes a few days. There are lots of long waits for reactions to proceed, and you'll find you need to go shopping for things you forgot. Also, what I tended to do is when I got a particular step to work, I'd rerun that reaction a bunch of times in a row to make a lot of the product for future steps. If you run a reaction the next day, you'll remember everything about it. And you will make mistakes in the later steps, destroying some of your intermediate product, so it's nice to have made enough to be able to recover and try again right away. The BrightStar synthesis led me to believe that the entire process might just take a couple of long days. I think it took me a month between purchasing the first chemical and "rolling" for the first time on my own stuff. I hope these notes will reduce your time significantly.
You can check yourself as you go along. For example, if the boiling points of your intermediate products are wildly out of line, you've screwed up. Note the expected colors, consistency, et cetera. One of the referenced documents on the web contains photos from the final production of MDMA from the ketone and nitromethane. They don't look very appetizing (other than the final photo of beautiful, brilliant, white crystals), but it's great to know that your gunk looks exactly like his gunk. You're going to eat the stuff later, right? Almost all the precursors are poisonous, right? You really would prefer to make something "edible", wouldn't you?
The scariest part, perhaps, is your first test of your first final product, unless you happen to have a mass spectrometer or an NMR in your basement (I don't). Luckily, I had tasted real MDMA previously, so I could taste the tiniest grain of my final product. Even though MDMA tastes pretty shitty, when my stuff tasted the same as the real stuff, it was the best-tasting thing in the world! Then, if you've got good sense, try a little bit for your first real dose -- perhaps a quarter of what you normally take (100 or 125 mg is a "normal" dose, depending on your weight, susceptibility, et cetera). Then try a half dose, then the whole thing.
I have seen "test kits" available that are presumably used to test street drugs to make certain that they're what they were sold as. I think that at least most of them are not highly specific tests; they simply indicate that the chemicals are in some general class. This might be good enough to tell you that the MDMA you bought is really speed or LSD in place of ecstasy, but if you've made the stuff yourself, it's pretty unlikely that you'll have speed or LSD in your final product by accident. Your precursors are all MDMA precursors, so the test kit is far more likely to "see" MDMA-like chemicals than other stuff, even if you totally screwed up. So it probably wouldn't hurt to run one of these tests, but it won't tell you for sure, and it certainly won't give you any indication of the purity.
I am completely paranoid, so, except for the totally safe reactions (and the way you'll know which ones are safe is by studying the reactions), I kept a fire-extinguisher handy. The only reaction that scared the shit out of me was the distillation of the nitromethane from the RC fuel. I did it outdoors, and for that one had the pin pulled on the fire extinguisher all the time.
Also, wear old clothes, with long sleeves, long pants, shoes and socks, and you might want to use rubber gloves when you're working with the highly corrosive stuff like muriatic acid, sulfuric acid, and sodium hydroxide. Safety glasses (or at least regular glasses, if you wear them) are a good idea for many steps. Although I thought I was being careful, I was not highly amused after working with the concentrated NaOH solution to find about a hundred tiny holes in my pants after washing them. I apparently splattered them with NaOH, and it ate a bunch of little holes...
I spent perhaps $300 on chemicals and, including a whole bunch of errors, made about 60 grams of pretty pure ecstasy. That's 600 doses of 100 mg. At $20 per dose, that's $12,000 worth. If you scrimp on the chemicals, perhaps you'll spend only $200, but a likely result is that you will then get $0 worth of ecstasy. The $100 savings nets you a $12,000 loss. I'm not much of a businessman, but that seems like a bad deal to me...
Get the right stuff if you can. Buy real dichloromethane (methylene chloride); don't mess with the Jasco stripper, since it's got alcohol and God knows what else in it. Use distilled water -- you can get it for a couple of bucks at the grocery store (or make it yourself, since you've got distillation glassware anyway). Get technical grade methanol, xylene, et cetera. You may spend an extra $100, but, again, that's just 5 doses of ecstasy. I used stuff like baking soda (NaHCO₃), Salt (NaCl), epsom salts (MgSO₄·7H₂O), et cetera, right from the grocery store or drugstore.
You can get a lot of the chemicals from mail order, Ebay, et cetera, but you will probably have to face some humans to buy stuff that's slightly suspicious. Don't volunteer stories of why you need them for your kid's science fair experiment -- just say nothing. It's good to have in mind some legal uses, but they won't ask. Don't get everything at once for two reasons. First, a complete grocery list for MDMA precursors is pretty suspicious, and second, the DEA in the US requires that large (over $100) purchases of chemistry supplies be reported to them. I got little bits everywhere, and made three trips to the lab supply place to get all my precursors (only two trips would have been necessary to keep the bills under $100 each, but, par for the course, I fucked up).
The main reason to go to a lab supply place is for the stuff that it's a pain to mail-order because of shipping constraints. Things like xylene are highly flammable, so it's much easier to get a gallon of that at the lab place than to hassle with the shipping. Similarly, muriatic acid is easy to get from a pool supply store, and get the nitromethane (mixed with methanol and castor oil) at a hobby shop.
Here's an idea I didn't use but you might: At the lab supply place, ask for the safety sheets on one or two of the chemicals. They're required to have them, and for some reason people think that if you're at all interested in safety then you're not the total degenerate that you really are.
Even when you're not at the lab supply, it feels "safer" if you know the lingo. At the pool supply place where you get the hydrochloric acid, don't ask for "hydrochloric acid"; ask for "muriatic acid". That's what pool people call it. God knows why. Similarly, in the hardware store, ask for "DampRid", not "anhydrous calcium chloride".
I know it feels like the time you were 16 years old and went into the drugstore to get "some chewing gum, some lifesavers, ..., oh, and a package of condoms", but you'll get over it.
Have enough ice on hand for the job. Again, ice is relatively cheap, so get an extra bag for each session. It's a royal pain in the ass to run out in the middle of some critical process. In addition to running ice water through the condenser for distillations, I also used ice in the bucket I used to recycle water through the aspirator. Ice water makes for a better vacuum, and the better the vacuum, the better your vacuum distillations will work. Remember that even when you are just using ice to cool a reflux column, you sometimes need to cool it for up to eight hours.
Work in a ventilated area or under a fume hood (since none of us have fume hoods in our houses, that means a ventilated area), especially when you're working with the stuff like the xylene, acetone, and especially with the HCl gas. In fact, do those outside if you can (definitely outside with the HCl). Look -- you're planning on causing enough brain damage as it is with the ecstasy; why add to it with xylene brain damage that doesn't even make you feel good?
Be patient -- for example, remember that every couple of drops of MDP-2-P that you toss away is a dose (perhaps a $20 street value) of ecstasy. When you're doing the separations, wait for the stuff to settle out properly, or you're throwing good stuff away. While you're waiting for a separation, I'm sure there's some glassware you can clean! And do use very clean glassware!
Get silicone grease to seal the distillation joints during vacuum distills. Make certain it's well sealed. If you turn on the pump and it leaks, turn off the pump, re-seal, and restart. If you don't, you're throwing away good stuff (or possibly toasting it, which is far worse). Brightstar, for example, recommends vaseline, instead of the silicone grease but I figure why not shell out a couple of bucks more and get exactly what works best.
If you screw up, don't continue without correcting the problem. Don't just assume that some of that brown gunk is what you wanted in spite of the fact that the instructions here say that you should be getting a bunch of brilliant white crystals. Before you start a process, be sure you know exactly how to do it. Read an organic lab techniques book on the subject -- it's amazing what you can learn and how much you can retain when you're sufficiently motivated.
If you are the least unsure, do a dry run before you commit the real chemicals. For example, just put water into the system and go through the motions the first time. I don't know what you'll learn, but I'm sure you'll learn something. I did a distillation of eugenol from oil of cloves just to make sure I knew how to do a vacuum distillation of an oil with a high boiling point before I committed my precious sassafras oil. You can get oil of cloves easily from a drugstore, and it's easy to look up boiling points of eugenol, et cetera. Similarly, if you've never used a separatory funnel, pour in some water and oil, shake it up, and then separate those. You'll learn to control the valve, you'll learn whether the valve needs greasing with silicone grease, you'll learn about venting, et cetera.
Be sure to get a good collection of jars that are easy to pour from. It's a giant pain to try to pour fluid from a jar and have it dribble all over your hands. (Guess how I learned this?) The Pyrex measuring cups are great for pouring. Some jars are; some aren't. Check them by pouring water from them before you put in stuff that you care about.
Beware of breaking the plug on the separatory funnel. If you're staring at the liquid and don't have your hand on the plug and the pressure builds up, it's certain to pop out when you're carrying it over a concrete floor. (Guess who broke his?) In fact, the glassware is all moderately delicate, so try to do anything you can to avoid putting it at risk. If you really are just beginning, hook up your various glassware arrangements over a soft bed the first time. Make sure stuff is securely clamped. Pay attention!
Read everything you can before you start. I read and re-read the entire synthesis many times, and then before I started any single step, I re-read it again, and kept a copy next to me as I worked. Notice that there are plenty of things you can do ahead of time -- make aluminum foil balls, "cook" MgSO₄·7H₂O (epsom salts) to make an anhydrous powder, et cetera.
Don't be in a hurry, especially for the last couple of steps. If you screw them up, you waste ALL your work. If you're going to be sloppy, do it at the beginning so you don't waste too much of your effort :^)
After I got the first working batch, I confess that I did the second batch in a "modified" state of mind, and it worked fine. I was able to keep everything in mind and under control, and, if anything, was able to concentrate better on what I was doing.

Stuff you'll need:

(I may easily have left something off this list; be sure to read the individual parts of the synthesis.) The recommended amounts below allow for a bunch of mistakes. Believe me; you'll make them. I started with a quart of sassafras oil, just to give you the scale, and used about 2/3 of it.

Chemicals:

Sassafras Oil: this is about 80-90% safrole. Look for aromatherapy supplies. You can get it on the web. Be sure to get 100% sassafras oil -- don't get it mixed with anything else. It's about $45 per quart, and a quart is vastly more than you'll need, but I'd get at least a half quart (I guess that's a pint).
MeOH (methanol, wood alcohol): I got mine from a lab supply house, technical grade. I'd get a gallon or two to account for fuck-ups. Maybe you can get it at drug stores, but all I've seen there is denatured ethanol and isopropyl alcohol. I eventually used two gallons.
Distilled H₂O: Distill it yourself, or get it at the grocery store. You'll need a few gallons (perhaps 5 or 6) by the time you're done. Get distilled water, not "spring water" or some other such shit.
p-Benzoquinone: Get this from photography supply shops. I got a pound and had plenty for a lot of trials.
Palladium(II)chloride (PdCl₂): Photography supply shops. This is expensive stuff ($25/gram). I got 5 grams total. Get exactly this -- not a replacement or a mixture of this and something else. You can do it 1 gram at a time, but the "recipe" below calls for 2. If you only have 2 grams, do two 1-gram batches.
DCM (methylene chloride; dichloromethane): I got it from a chemical lab supply house, technical grade. I used less than a gallon.
Xylene: Chemical supply house. I used technical grade, and eventually went through an entire gallon.
Acetone: It's with the paint thinners in a hardware store. I got a gallon and it was more than enough. Mostly, I used it to wash and dry glassware, but you also need a little bit for the final wash of the sacred chemical.
NaCl (non-iodized table salt): grocery store. Be certain it's not iodized. I don't know what the iodine would do, but I have a healthy imagination, and none of the things I could imagine were good. I think almost all salt (maybe not kosher salt) contains sodium aluminum silicate. Mine did, and that didn't seem to cause any problems. It's cheap -- get three pounds.
NaHCO₃ -- Sodium bicarbonate (baking soda): grocery store. One big box is plenty.
NaOH (lye): I used Red Devil lye from a grocery store (drain cleaner). Get pure, dry lye. Not Drano with the little aluminum flecks, or anything that's already dissolved. Get three or four cans of the stuff.
HCl (hydrochloric acid, muriatic acid): Get this from a pool supply place. I got a gallon, and it was far more than enough. It's cheap. Get a gallon or two.
MgSO₄·7H₂O -- Magnesium sulfate: These are epsom salts. Get them at a drugstore. You'll need to cook it to get rid of that "·7H₂O". I bought the amount that fits in a container that's the size of a half-gallon milk carton.
Nitro RC fuel: From a hobby shop that sells fuel for the RC models. I got a gallon for around $30, and it was far more than I needed. Get the highest concentration you can. The best I found was (supposedly) 40%. It's a mixture of nitromethane, methanol, and something like castor oil. I hear that even higher concentrations are available. The kid that sold me the 40% stuff seemed really concerned that I'd ruin my model airplane engine using such a high concentration. I assured him that I'd dilute it with some methanol -- yeah, right.
Aluminum foil: I used the "extra heavy duty" Reynolds wrap. One roll from the grocery store is plenty. Apparently the stuff called "heavy duty" also works, but I assume the reaction will run faster (and hotter and scarier) with it. Everybody cautions against the regular foil. It is just too thin, and believe me, you don't want to see that reaction "run away". It barrels along at a pretty heart-stopping rate even with the extra heavy duty stuff.
Peanut oil: Grocery store. Get a couple of quarts.
Safflower oil: Grocery store. A little bit; all you need is a few ounces. Be sure to get the stuff with NO ADDITIVES since it's going to get hot and be mixed with something you eventually eat!
HgCl₂ (mercuric chloride): From a photo chemical supply place. You don't need much -- 3 or 4 grams is plenty. I think I got an ounce and used only a tiny amount. Maybe there's some way I can feed the rest to certain politicians. Careful: this stuff is REALLY poisonous.
Sulfuric Acid: I used the high-powered drain cleaner. I got it from a hardware store. I used less than a quart. I don't need to say "be careful", do I?
CaCl₂ (Calcium chloride): I used "Damp-Rid" that I got from a hardware store. It's with the mildew prevention chemicals. One cannister is plenty.

Apparatus:

Be sure it all fits together. I used 24/40 connectors throughout. The 24/40 seems to be the most easily available stuff, and it seems quite suitable for the quantities of chemicals you'll be using. If you already happen to have larger or smaller stuff and just need a piece or two, go ahead and use that, but if you're starting from scratch, get the 24/40 size.
If you haven't done this sort of thing for awhile (or ever), obtain a manual on organic lab techniques. Read through the appropriate section before you begin using any technique. Of course you'll screw up anyway, but this way you'll screw up a couple of fewer times. The manual recommended by many illicit chemists is this: "The Organic Chem Lab Survival Manual ", by James W. Zubrick. Others work fine, too.
For me, at least, it was critical to have something like the "CRC Handbook of Chemistry and Physics" or the "Merck Index" to look up physical properties (especially boiling points) of such things as methanol, acetone, safrole, eugenol, ...) It gave me a warm, fuzzy feeling when the stuff would distill at the correct temperatures, and when there was a problem, I'd know about it.
You can find lots of this apparatus on the internet, and can sometimes get good prices on places like Ebay on used glassware.
Glassware:

1000 ml 2-neck round-bottomed flask (RBF)
500 ml RBF
distillation head
vacuum adapter
thermometer coupling
vigreaux column
distillation column
separatory funnel: at least 1000 ml -- 2000 or 4000 ml is better.
addition funnel: at least 100 ml
2000 ml two-neck RBF (not required, but nice)

(If you're lucky, you may be able to find a separatory funnel with a 24/40 fitting at the end that you can use as an addition funnel as well. I was not lucky, so became the proud owner of yet another piece of glassware.)
Other Stuff:

Buchner filter, filter flask, flask stopper, filter paper.
Coffee filter + filter paper
Combination hot plate/stirrer. You can't get away without this, especially for the final step, and it makes life a lot easier if you have it at the beginning. I got mine late and was sorry.
Magnetic stir bar (get one that's egg-shaped and works in RBFs)
Clips to hold the glassware together.
Two lab stands and at least two clamps. Don't skimp on the clamps -- they hold hundreds of dollars worth of glass!
Aquarium pump (to pump ice water through distillation column)
Thermometer that fits coupling (0-300 degrees). It's nice to have two -- one to watch the temperature of the stuff that's coming over in the still, and another to check other temperatures, like the temperature of the peanut oil, or of the fluid that you are distilling.
Boiling stones. You can often avoid using these if you've got the hotplate/stirrer. The spinning stir-bar works better than boiling stones under vacuum conditions, since there tends to be a lot less "bumping". If you've never seen bumping, let me tell you a secret: the first time it happens to you, you'll be very upset.
Silicone grease
Vacuum pump. I used a spa pump with enough pipes to take water out of and return it to a 5 gallon plastic bucket.
Plastic tubing (3 pieces -- two to connect to the input and output of the distillation column; one to connect the aspirator to the vacuum adapter, or to the flask holding the buchner funnel). Make sure they're long enough. I used 2 sections that were about 2.5 feet and one of 6 feet.
Measuring cups and/or graduated cylinders. I used a 500 ml cylinder plus a 50 ml cylinder.
Triple-beam balance.
Glass wool (I got a furnace filter and cut out chunks of the wool). I used it to plug the vigreux column when it was filled with glass beads and calcium chloride).
Lots of clean glass jars for storage. Next time I'd just get a dozen mason jars (quart size) with lids. Some smaller jars are good, too.
Tiny spatula for measuring out tiny amounts of dry chemicals.
Glassware cleaning brushes. Get at least one curved one for cleaning the insides of the round flasks, and one straight one.
Glass beads to fill the vigreux column for fractional distillations. The people at the hippie store that sold all sorts of psychedelic colored beads thought it was pretty strange when I looked over everything and finally selected the ugliest (and of course cheapest) beads for my "creation".
Coffee grinder (to ball up the aluminum foil) Please clean out the coffee grounds first, and PLEASE clean out the aluminum dust afterwards.
(optional) paper shredder (to shred aluminum foil)

Synthesis notes

(All temperatures below, unless mentioned otherwise, are centigrade.)
Overview:

I distilled sassafras oil to make safrole.
I distilled RC model fuel to make nitromethane.
I used the Wacker reaction to make MDP-2-P from the safrole.
I made MDMA from the MDP-2-P and the nitromethane.
I took the ecstasy. This step was more fun than all the other steps put together!

Safrole:
There seems to be no problem with the distillation of the safrole from the raw sassafras oil using Bright Star's recommendations.
If a ¾ horsepower pool pump is used, it appears that the temperature at which the safrole comes over is about 106-107°C on the first pass. For the second pass, I used a vigreux column in addition, and the safrole came over at between 94°C and 99°C. Good vacuum! The pump basically recirculates water through an aspirator as fast as it can using water in a 5 gallon plastic bucket. To get a higher vacuum, there was always ice in the bucket. Thus the temperature of the recirculating water was always 0°C (unless I ran out of ice).
There are a couple of photos on the web of designs for good vacuum pumps that recirculate water. I mounted my pump to a board and then attached pieces of PVC pipe to make an output that sprayed into the bucket, and an input that sucked water from the bucket. I did not, therefore, need to drill any holes in the bucket as was proposed in at least one of the web designs.
The suction also seemed to be vastly better if there was a baffle in the plastic bucket to keep the air bubbles from getting sucked into the input of the pump. I used the lid of the bucket as a baffle and crammed it down vertically between the place where the water from the aspirator fixture sprayed in water/bubbles and the input pipe from the spa pump sucked it out. This uses ice very quickly -- without ice, it's amazing how fast a ¾ horsepower motor heats up 4 gallons of water. By the way, a ½ horsepower motor should be sufficient; I just happened to have one rated at ¾ horsepower.
Also, always run ice water through the distilling column, either when distilling or when you're using it as a reflux column.
Distilled the sassafras over peanut oil in a 1000ml flask in 2 passes. The result was about 700ml of safrole from 1 quart of sassafras oil.
Nitromethane:
Bought nitro fuel for RC engines at a model hobby shop. The bottle said it was 40% "nitro" (= nitromethane), but after my distillation, I doubt it. It seemed to be at most 30%. Had to do a fractional distillation using a vigreaux column. The fuel is a mixture of methanol, nitromethane, and castor oil.

Note by Rhodium: This discrepancy is probably due to the fact that methanol and nitromethane forms an azeotrope. First a 92:8 MeOH/MeNO₂ mixture (bp 64.5°C) distills over (close to the boiling point of pure methanol, bp 64.7°C) and when all the methanol is gone, the temp shoots up to ~100°C, where pure nitromethane is collected.

Nitromethane boils at 101°C, so I had to do it over cooking (peanut) oil instead of water. It seemed to come over at about the right temperature, but it's OK to have a mix of the nitromethane and some methanol, since the only time the nitromethane is used is in a mixture that uses methanol as a solvent, and the total amount of methanol is unimportant, so some extra is OK. If there is some methanol, however, it may be important to add a bit of extra nitromethane/methanol to be sure to get enough nitromethane, since that's critical to making the final product. I used about 10% or 15% more of the mix for that final step and didn't have any problems.
What I did was to distill for a long time to get almost all of the methanol out, and then, when the temperature spiked up to near 100°C, I let that run for a few seconds, then switched to a new flask to get the nitromethane.
Did I mention that this distillation scared the shit out of me?
What frightened me about the nitromethane is that the Merck Index says that it has a "flashpoint" at 112°F. I don't know what a flashpoint is, but I didn't want to find out! Nitromethane is the "nitro" in "nitro-burning dragsters" -- you know, those drag-racing cars with all the flames coming out. Note that the flashpoint is far below the boiling point (about 101°C) of nitromethane.

Note by Rhodium: This is not something of concern. The flash point of a substance is simply the lowest temperature at which you can ignite a substance. Gasoline has a flash point at several tens of centigrades below zero for example. It does not mean that the compound will spontaneously ignite or detonate, just that you should avoid sparks or open flames (which is a good rule at all times in a lab).

I tried to distill with a vacuum, and it was very difficult with boiling stones, since there would be a huge "bump" as a huge chunk boiled at once, which reduced the pressure, which had to build up for another huge bump. I did not have my hotplate/stirrer at the time, so I couldn't tell exactly at what temperature it was boiling, and the temperature was all over the place. Next time (if there is a next time), I'll try the vacuum distill, but with the stir-bar twirling like a dervish, and I'll use a vigreux column crammed with glass beads for a good fractional distillation.

Note by Rhodium: Distillation of nitromethane at atmospherical pressure is not inherently dangerous as long as you aren't distilling it all to dryness. It is not practical to vacuum distill nitromethane, as there is too much loss of product down the drain (using an aspirator as vacuum) or into your pump oil.

MDP-2-P (the "ketone"):
Used Methyl Man's "Benzoquinone Wacker Oxidation of Safrole in Methanol".
I tried the long-term stirring of the PdCl₂ in methanol for 6 or 7 hours before adding the water and the p-benzoquinone. You can get the p-benzoquinone and PdCl₂ from photography supply places. I mail-ordered mine from a Canadian lab (I thought this was great, too, since I'll bet the DEA has a harder time looking at Canadian lab records). PdCl₂ is expensive -- like $25 per gram.
I never needed to add heat -- just a slow addition and then a long wait afterwards (8 hours to be sure everything reacted). Stirred the whole time.
I used gravity filtration in a coffee filter to get rid of the hydroquinone, and then put the filter in a zip-lock bag and squeezed it to get out the last drops.
When I washed with the sodium bicarbonate, I had a lot of crud on the interface between the DCM and the methanol fractions, but it was workable. The saturated NaCl made a real mess -- emulsion-like that just wouldn't separate. I finally froze it to break it up. I only did one NaCl wash since it was such a pain. Maybe it would be better not to shake the mixture so hard in the separatory funnel. Or maybe it would be better to use distilled H₂O for the mixes. Or both. Next time, I'd use only distilled H₂O for every place I need water, and I wouldn't shake so hard on this wash.
I did distill in two steps -- DCM over water without vacuum, then the MDP-2-P under vacuum over oil. Did it with a stir-bar and it worked OK unless I lost vacuum. Stir bar works much better than boiling stones, especially under vacuum.
I had problems cleaning the RBF afterwards, due to some charred shit. I read later that the best way to clean this is to add some paint thinner (mineral spirits) and clean with that FIRST, before you try stuff like soap and water (and strong acids, strong bases, et cetera). I do know the mineral spirits don't work so well afterwards...
MDMA:
Used Methyl Man's "Reductive Amination of MDP2P with Al/Hg + Nitromethane".
The reason I used this approach is that I was totally unable to make the methylamine hydrochloride (methylammonium chloride, MA.HCl) by any method. I tried BrightStar's method, as well as about 4 other methods I found on the web. In all cases, I was able to make what were probably mixtures of MA.HCl and ammonium chloride, but I couldn't figure out how to assess the purity. I also didn't have any luck getting the stuff I needed to do a purification: absolute ethanol is difficult to obtain; in California, the best you can purchase at a liquor store is about 75%, so you're faced with a distillation even to get to 95%. Then you've got to get some anhydrous calcuim oxide, and I didn't know how to do that. I even made a bunch of chloroform to clean out other impurities (which you should do), and that was a pain in the butt and perhaps a bit dangerous, too.
The problem is that the ammonium chloride will cheerfully react by the same mechanism as the MA.HCl with the MDP-2-P, but it will make MDA in place of MDMA. I would not have minded a mixture of, say, 3% MDA and 97% MDMA, but I just didn't know what I'd get. Anyway, the method described below worked perfectly, and should make exactly 0% MDA and 100% MDMA.
At first I didn't have a 2 liter, 2 necked RBF, so I did half-batches in a 1 liter flask, and that worked great, except that it took, of course, twice as long. There was never a problem with run-away reactions, and I always got a happy result. The full version is a little more tempermental, left more aluminum junk, but worked fine, too. Do this reaction at the end of the day, and let the final stuff sit around all night to make sure the reaction is complete. If you try to do it after just, say, four hours, there will be some aluminum fragments that are still bubbling in the NaOH, and these are a real pain in the butt during the separations. Wait overnight and everything is cool...
I used not only heavy aluminum foil, but the "Extra Heavy Reynolds Wrap". You can just cut 3 inch strips from the roll and put them through a paper shredder (to make pieces that are 3 inches long and ¼ inch wide) -- this is much easier than cutting them by hand. You'll have to do some dicking around with the coffee grinder to figure out how much of the foil strips can go in at once and not jam the machine. Even with the paper shredder and coffee grinder, it takes surprisingly long to make enough little foil balls to run the reaction.
After the reaction, I poured the grey sludge into large (gallon-sized) bottles, and added the xylene (xylene works fine instead of toluene, by the way) to the bottle. Then I did all the shaking in there before pouring the stuff in a separatory funnel.
I tried the washes with tap water and there was always a lot of gunk. On my final pass, I used distilled H₂O in all steps and things were MUCH better. The moral: use distilled water, don't use tap water!
When you are drying the epsom salts (do this well ahead of time), don't put too much in the oven at once. I put a thin layer on a sheet of aluminum foil and cooked it very hot (400°F) in an oven for an hour or so. I made a bunch of batches and kept them sealed tightly in a jar. I also ground the stuff to a powder using a mortar and pestle. I might try a coffee grinder next time. Don't try to cook up too much at once -- this can make a horrible mess.
I used a hair-dryer to dry the bottles that were to contain the anhydrous stuff (after the acetone wash, of course).
I had two bad experiences with HCl generators before I figured out how to do it. This is the way: Add NaCl (lots, non-iodized) to a two-necked flask. A big one (2 liters) is good. Wet the NaCl with HCl, but not too much (no puddles).
Plug a vigreaux column with glass wool (cut from a heater filter), and pour the column full of CaCl₂ (Damp-Rid pellets). Then put the thermometer adapter with a tube instead of a thermometer mounted in it into the top of the column.
Into the other neck of the main flask, put in an addition funnel with concentrated sulfuric acid. All joints should be greased with silicone lubricant. Drip in the H₂SO₄, and anhydrous HCl gas comes out the tube. Do this outdoors -- you're going to get clouds of HCl gas, which you certainly don't want to breathe. Use the silicone grease throughout.
Even at the end, when I thought there were no longer any mistakes to make, I screwed this up. I tried to powder the CaCl₂ to get better surface area, and then tried to pump through too much HCl gas too quickly. The powder was too fine, it plugged the gas, and finally a giant belch of gas, H₂O, and CaCl₂ was dumped into the xylene and it totally fucked up the batch. TAKE IT EASY AND SLOW WITH THE GAS GENERATION. You have plenty of time, and it's the last step.
TEST THE TUBE AND EVERYTHING IN XYLENE BEFORE YOU TRY IT FOR REAL! I found, to my horror, that the "aquarium rock" that I added to the end of the tube to make lots of tiny bubbles dissolves in xylene. I had great success with nothing but a hollow tube.
Don't be a pig -- when you get a bunch of precipitate, run it through the filter and then re-gas. It's even better to chill the xylene mixture to drive out more precipitate. At some point, usually after about 3 gassings, the stuff in the xylene starts getting a yellow tinge and then starts to stink like HCl (maybe water in the xylene?) Anyway, I did it in three passes, and as soon as I saw a tiny amount of yellow, I quit. You can use the slightly yellowed stuff -- wash it with acetone, but the more yellow and the more stink, the more of the real product seems to disappear and be dissolved in the water.
When you get the final stuff -- MDMA mixed with xylene -- get as much xylene as you can out of it on a vacuum filter (returning the xylene, possibly, for another passing of the HCl gas). Then, over the vacuum, put in a few jolts of acetone. This dissolves not only the yellow crap (if there is any), but tends to pull out the xylene and things dry quite rapidly.
I got (on the time I made the fewest errors) about 18 grams of MDMA (dried from the acetone) from 25 ml of ketone.
I did not recrystallize this "raw product", since it looked snow-white to me. It does have a faint odor (safrole?) but very faint.

Note by Rhodium: Even if your product looks pure and snow-white to you, please do yourself and your friends a favor and recrystallize the product. A lot of unhealthy byproducts are white/colorless just like pure MDMA, so visual inspection cannot be used to verify purity (you can only verify the presence of colored impurities). Pure MDMA·HCl is odorless, so using your nose is a better way to gauge purity.

The bioassay was extremely successful (I tested perhaps 120mg of acetone-washed product on a human subject weighing about 170 pounds).
Making Doses:
This was a pain. What I finally wound up doing was to take the pile of dried stuff, chopped it with a razor, crushed it with a piece of shiny plastic, chopped again, and got pretty good dust. Then I packed the dust in the most consistent repeatable possible way into capsules. Then I counted the capsules, weighed the whole mess, then weighed that many empty capsules. Thus I determined the dose for each, and wrote that down with the capsules.
Although it's obviously an approximation, if I know that the average capsule in a batch contains 270mg of MDMA, I can pour out that capsule on a sheet of glass, chop it with a razor, and form the powder into a fairly uniform rectangle. Then it's easy to cut out roughly what I want. If you divide the 270mg into thirds, you know that each is about 90mg, et cetera.
A method to measure a known quantity is with an empty capsule and a cylindrical stick or something to pack the stuff solidly into the bottom. I used a drill index and was able to find a perfect sized drill bit for my capsules. Then you can measure the height of the stuff in the capsule pretty accurately.
I made a big error the first time I was loading a bunch of powder into capsules. It took a fair amount of time, and I took a bunch of breaks. I couldn't bear to wash that beautiful white powder off my fingers each time, so I licked them clean. I have no idea what my final dose was that day, but I know it was higher than anything I've taken before or since. The next time I was fairly anal about doing the whole job all at once, followed by a single final lick, (and then 120mg from a capsule, just to make sure).

Stránky

pondelok 17. septembra 2018

safrole

beilstein/crossfire search

A Study of the Precursors, Intermediates andReaction Byproducts in the Synthesis of MDMA

R.J. Renton, J.S. Cowie and M.C.H. OonForens. Sci. Int. 60, 189-202 (1993)

Abstract

Introduction

Experimental

Materials

Syntheses

Analytical techniques

HPLC

GC-MS

Other techniques

Results and Discussion

MDMA and intermediate compounds

Reaction by-products

Route I.

Route II.

Applications

Conclusion

References

A Note about some Impurities in Commercially Available Piperonylmethylketone

By AMA Verweij and AGA Sprong Microgram 26(9), 209 (1993)

Introduction

Experimental

Results and discussion

Table 1

References

Synthesis of MDP2P From 1,3-Benzodioxole by Friedel-Crafts Alkylation with 2-Nitropropene

Written by Scooby Doo

Pseudonitrosite FAQ

by Rhodium

Introduction

Theory

Experimental

Pseudonitrosites4,5,7

Phenyl-2-nitropropenes4,5,7

References

Photoamination of Methylstyrenes

The Possible One-pot-shot From Isosafrole to MDMA

General method for the production of amphetamines from methyl styrenes, lifted from the literature.

Proposed experimental method.

Bibliography: a reading list of the good stuff

Links to other selected photochemistry (and otherwise related) web pages.

MDMA via Tosyl Chloride Intermediate?

Synthesis of MDMA by Addition of Methylamine to1-(3,4-Methylenedioxyphenyl)-2-Propanol Tosylate

Ollie-RSM

Siegfried

Tr-E-frog

Ritter

Siegfried

Siegfried

Ritter

MDA from Bromosafroleusing a PTC and an azide intermediate

by Ritter

Procedure1

Notes:

Synthesis of MDE from 2-Azidosafrole

Example using cyclopentyl azide2

Synthesis of MDMA from 2-Azidosafrole

Sample procedure3

References

A Working MDMA (Ecstasy) Synthesis

By Doctor Drool

MDMA Synthesis Story

Introduction:

Overall notes:

Stuff you'll need:

Chemicals:

Apparatus:

Synthesis notes

A Study of the Precursors, Intermediates and
Reaction Byproducts in the Synthesis of MDMA

R.J. Renton, J.S. Cowie and M.C.H. Oon
Forens. Sci. Int. 60, 189-202 (1993)

By AMA Verweij and AGA Sprong
Microgram 26(9), 209 (1993)

Synthesis of MDP2P From 1,3-Benzodioxole
by Friedel-Crafts Alkylation with 2-Nitropropene

Pseudonitrosites^4,5,7

Phenyl-2-nitropropenes^4,5,7

Synthesis of MDMA by Addition of Methylamine to
1-(3,4-Methylenedioxyphenyl)-2-Propanol Tosylate

MDA from Bromosafrole
using a PTC and an azide intermediate

Procedure¹

Example using cyclopentyl azide²

Sample procedure³