Isolation and structural determination of non-racemic tertiary cathinone derivatives

Article abstract of DOI:10.1039/c5ob01306b

The racemic tertiary cathinones N,N-dimethylcathinone (1), N,N-diethylcathinone (2) and 2-(1-pyrrolidinyl)-propiophenone (3) have been prepared in reasonable yield and characterized using NMR and mass spectroscopy. HPLC indicates that these compounds are isolated as the anticipated racemic mixture. These can then be co-crystallized with (+)-O,O′-di-p-toluoyl-d-tartaric, (+)-O,O′-dibenzoyl-d-tartaric and (-)-O,O′-dibenzoyl-l-tartaric acids giving the single enantiomers S and R respectively of 1, 2 and 3, in the presence of sodium hydroxide through a dynamic kinetic resolution. X-ray structural determination confirmed the enantioselectivity. The free amines could be obtained following basification and extraction. In methanol these are reasonably stable for the period of several hours, and their identity was confirmed by HPLC and CD spectroscopy.

Full text of DOI:10.1039/c5ob01306b

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Isolation and structural determination of
non-racemic tertiary cathinone derivatives†
Cite this: DOI: 10.1039/c5ob01306b
M.-J. Zhou,a S. Bouazzaoui,a L. E. Jones,a P. Goodrich,a S. E. J. Bell,a
G. N. Sheldrake,a P. N. Horton,b S. J. Colesb and N. C. Fletcher*a,c
The racemic tertiary cathinones N,N-dimethylcathinone (1), N,N-diethylcathinone (2) and 2-(1-pyrrolidi-
nyl)-propiophenone (3) have been prepared in reasonable yield and characterized using NMR and mass
spectroscopy. HPLC indicates that these compounds are isolated as the anticipated racemic mixture.
These can then be co-crystallized with (+)-O,O’-di-p-toluoyl-D-tartaric, (+)-O,O’-dibenzoyl-D-tartaric
and (−)-O,O’-dibenzoyl-L-tartaric acids giving the single enantiomers S and R respectively of 1, 2 and 3, in
the presence of sodium hydroxide through a dynamic kinetic resolution. X-ray structural determination
confirmed the enantioselectivity. The free amines could be obtained following basification and extraction.
In methanol these are reasonably stable for the period of several hours, and their identity was confirmed
by HPLC and CD spectroscopy.
Received 26th June 2015,
Accepted 5th August 2015
DOI: 10.1039/c5ob01306b
www.rsc.org/obc
4-methylmethcathinone or “mephedrone” have been shown to
Introduction
be considerably more potent.6,7 The latter has become a major
Because of both market trends and legislative controls, there international concern,8 being the first of many derivatized
has been an increasing number of recreational ‘designer’ cathinones to be identified in drug seizures and commercially
entactogenic drugs available on the market, often miss sold as available products sold under a variety of guises such as “plant
“legal highs”.1,2 In particular, β-ketone derivatives of amphet- food” or “bath salts”.9–11 Yet an understanding of both the
amine, commonly known as “cathinones”, have been found in long, and short-term pharmacological effects of many of these
many samples analysed forensically (Fig. 1).3,4 Cathinone itself recently identified materials is limited which is, in part, due to
is a stimulative alkaloid found in Catha edulis, or Khat, widely the difficulty in obtaining pure characterized materials from
cultivated in Eastern Africa and the Arabian Peninsula,5 but reliable sources.
the synthetic N-methylated derivatives methcathinone and
The forensic identification of the ever-expanding range of
cathinone derivatives has relied upon GC/MS detection against
known standards, however the rapid proliferation of these new
materials means that routine identification is now a consider-
able challenge.12–15 Several new techniques are now being
applied to both rapidly screen seized samples,16–19 and to
identify metabolized products.20–23 These include electro-
chemistry24 and the use of SERS Raman spectroscopy studied
by both Mabbott et al.25,26 and ourselves,27 in addition to the
traditional chromatographic mass spectrometric techniques.
The availability of legitimate synthetic procedures has, until
relatively recently, also lagged behind the presence of these
new substances in the market place.6,7 Studies have now
shown that a wide range of cathinone derivatives can be
reliably obtained using a synthetic pathway initially reported
in 1950 28 via the acid-catalyzed bromination of the appropri-
ate aryl ketone, followed by amination to give the target as a
racemic product.29–37
Fig. 1 The structure of β-ketone derivatives of amphetamine;
cathinones.
aSchool of Chemistry and Chemical Engineering, Queen’s University Belfast, David
Keir Building, Belfast, Northern Ireland, BT9 5AG, UK
bUniversity of Southampton, Chemistry Department, EPSRC National
Crystallography Service, Southampton, SO17 1BJ, UK
cDepartment of Chemistry, Lancaster University, Bailrigg, Lancaster, LA1 4YB, UK.
E-mail: n.fletcher@lancaster.ac.uk
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra,
The majority of the seized derivatized cathinone materials
are assumed to be racemic, although there has not been a sys-
tematic study to demonstrate this. They are normally obtained
additional CD spectra for compounds 1–3 and HPLC traces for the separated
enantiopure species 1–3. CCDC 1407691. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c5ob01306b
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in a stable protonated solid form, generally assumed to be the from aqueous solution. The tertiary amines, unlike the amphet-
chloride salt. As the free amine, cathinone derivatives are amine analogues appear to have a significant pharmacological
unstable to decomposition, and undergo racemization due to effect,37,54 presumably because of the greater lipophilicity. In par-
keto–enol tautomerism.3 Calculations have predicted the pKa ticular, the pyrrolidine function has been identified in a number
to be in the range of 8.4 to 9.5, suggesting that these com- of materials being regularly found in forensic analysis such as
pounds remain protonated at physiological pH, and unlike the 4-methylpyrrolidinopropiophenone (MPPP), pyrovalerone and
analogous amphetamine derivatives, it is predicted that the 3,4-methylenedioxypyrovalerone (MDPV).9–11 Importantly to this
ketone group increases both the planarity of the compound, study, they appear to be more stable to decomposition in com-
and the hydrophilicity so lowering their activity with respect to parison to the primary and secondary amines permitting deter-
the parent amphetamine, being less likely to cross cell mem- mination of their enantiopurity with relative ease.
branes.38 Despite these limitations, studies have shown that as
with amphetamine, S-(−)-cathinone and S-(−)-methcathinone
have
a greater pharmacological effect in rats over the
Results and discussion
R-forms,6,39 although the pharmacological effects appear to be
species dependent.40
The targeted tertiary amines N,N-dimethylcathinone (1), N,N-
To gain a good understanding of the pharmacological diethylcathinone (2) and 2-(1-pyrrolidinyl)-propiophenone (3)
effects of these cathinone derivatives, and to possibly gain a were prepared via 2-bromopropiophenone using an adapted
forensic advantage on seized materials, a range of chromato- procedure previously reported for the preparation of ( )-4′-
graphic techniques have been considered for their enantio- methyl-2-bromopropiophenone,31 giving characterization data
meric separation. These include using HPLC with either a consistent with that recently reported by Smith et al.24 This
chiral stationary phase41–44 or a chiral additive to the eluent,45 compound is a severe lachrymator and should be handled
GC following chiral derivatization of the analyte,30,42,46–48 with extreme care. This was then readily converted to com-
capillary electrophoresis,49–52 and NMR spectroscopy using pounds 1, 2 and 3 by the addition of just under a stoichio-
appropriate chiral auxiliaries.30,53 However, many cathinone metric amount of either dimethylamine hydrochloride or
derivatives, particularly those with larger groups appended to diethylamine hydrochloride in an excess of triethlyamine, or
the nitrogen do not readily provide clear baseline chromato- pyrrolidine respectively in reasonable yields (60 to 85%).37,54
graphic separation, and can decompose/racemize in the The identity of compounds 1, 2 and 3 were confirmed by both
process. Consequently these techniques are unsuitable to 1H NMR and 13C NMR spectroscopy (Fig. S1–3†), as well as
provide enantiopure materials in reasonable quantity. S-(−)- high resolution TOF EI mass spectrometry. In comparison to
N,N-Dimethylcathinone,37,42,54 S-(−)-N-methylcathinone6,29,30,42 N-methylcathinone and mephedrone previously prepared by
and S-(−)-cathinone55 have however been isolated from the ourselves,27 the free amines of 1, 2 and 3 were observed to be
natural products R/S-N-methylephedrine, R/S-ephedrine and considerably more stable to decomposition, however they were
R/S-norephedrine respectively by either permanganate or chro- stored under nitrogen and at −30 °C prior to use.
mate oxidation. This route does limit the isolation of enantio-
The addition of a non-racemic chiral acid should permit
pure materials to the availability of naturally occurring the selective co-crystallization, with the preferential formation
precursors, and potentially results in products contaminated of a single diastereoisomer. Enantiopure (+)-O,O′-di-p-toluoyl-
with carcinogenic metal ions. Osorio-Olivares et al. also D-tartaric acid (D-DTT) was initially investigated, in a range of
demonstrated that non-racemic cathinone derivatives can be stoichiometries, with the best results found using one equi-
isolated with high enantiopurity via a Friedel–Crafts acylation valent of the di-acid relative to the cathinone derivative,
of substituted aromatic systems with S- or R-N-trifluoro-acetyl- alongside one equivalent of sodium hydroxide on the rationale
alanyl chloride.56 Whilst the chloride salt of these non-racemic that the orientation of the two aromatic functions could
materials appear to be stable over several months, it is enhance the diastereomeric differences through π-stacking
reported that racemization is possible during basification in interactions from the aqueous solution, consistent with the
the final isolation of a free amine.52
ideas previously reported by Berrang et al. with ( )-norephe-
To investigate the possibilities to obtain non-racemic cathi- drine.55 This proved to be correct, with good quality crystals
none derivatives preparatively, we report here a method to forming over the period of several days. Attempts were made to
separate three cathinone derivatives with tertiary amines optimize the conditions using a small amount of sodium
groups (Fig. 2) by co-crystallization of the protonated forms hydroxide solution to encourage solubility of the selected
chiral anions (Scheme 1). No success was observed however
with organic acids such as L-tartaric acid, or (1S)-(+)-10-cam-
phorsulfonic acid in keeping with earlier studies observed
with cathinone itself.55
With D-DTT in the presence of sodium hydroxide and com-
pound 1, needle like crystals (1-D-DTT) readily formed follow-
ing the evaporation of the acetone in a yield of up to 68%. The
Fig. 2 Identity of compounds rac-1, 2 and 3.
yield itself was initially surprising assuming that the observed
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Scheme 1 The route to enantio-separation of cathinones 1, 2 and 3.
process is a diastereoselective crystallization. However given the S-isomer (Fig. 3). The stereochemistry was assigned relative
the possibility of a degree of racemization occurring in the to the starting tartaric acid and whilst only one crystal was
basic solution, presumably by keto–enol tautomerism,3 the evaluated, the morphology was consistent with the bulk
selective removal of one enantiomer allows re-equilibration sample. The close contact between the cathinone amine and
providing opportunities for a dynamic resolution, and a yield one of the two tartaric carboxylic acid groups is 2.708 Å,
of up to 78% was recorded in the case of 2-D-DTT. However, suggesting a hydrogen bond, and possible displacement of the
lower yields, typically 22% (3-D-DTT) were obtained in many acid proton to the nitrogen in the solid-state. Interestingly for
cases, especially with compound 3, as the product was isolated the cathinone itself the aromatic ring, and the ketone are close
before complete precipitation had occurred. It was observed to being planar, with a torsion angle of 19.38°, bringing the
that if a longer period of time was required for the crystalliza- ketone and amine in close contact (2.521 Å). These findings
tion procedure, the product darkened in colour, resulting in are in keeping with the calculations reported by Gibbons
poorer quality crystals/precipitates, presumably caused by et al.38 and the previously reported hydrogen chloride salt of
partial decomposition of the parent cathinone. The 1H NMR both mephedrone and pentedrone.57 The tartaric acid itself
solution spectra of the co-crystallized products indicated that has a trans configuration enabling a chain like hydrogen
in each case a one to one stoichiometry of one cathinone is bonded conformation with itself (2.469 Å) along the b crystallo-
associated with one D-DTT (DMSO-D6; Fig. S4–S12†). Similarly, graphic axis and a secondary N–H–O hydrogen bond with the
the electrospray mass spectrometry confirmed the association ketone (Fig. 4).
through the detection of the ion pairs at 564.2187 and
Converting the crystalline salts back to the free amines
590.1918 for 1-D-DTT and 3-D-DTT respectively, although the allowed analysis of the enantioselectivity of the co-precipi-
dominant species in each case was unsurprisingly the proto- tation with the aromatic tartaric acids. This was achieved by
nated cathinone itself.
dissolving a small quantity of the crystals up in dilute aqueous
Following the initial success with D-DTT, both (+)-O,O′- sodium hydroxide solution and extraction into dichloro-
dibenzoyl-D-tartaric and (−)-O,O′-dibenzoyl-L-tartaric acids methane followed by evaporation. Given that the compounds
(D- and L-DBT) were also considered under the same conditions
resulting in colourless crystals with compound 1 giving
1-D-DBT and 1-L-DBT respectively. Compounds 2 and 3 again
took longer to crystallize typically giving coloured precipitates
rather than distinct crystals suggesting that a larger functional-
ity on the nitrogen atom frustrates the crystallization process.
Similarly, the quality of the material obtained using L-DBT was
significantly lower than those obtained using either the D form
or with D-DTT, which was assumed to arise from the margin-
ally lower enantiopurity (97%) of the starting material used.
For each of the salts obtained, a one to one stoichiometry was
1
again confirmed by both H NMR spectroscopy and the elec-
trospray mass spectrometry.
The X-ray structural determination of 1-D-DTT similarly con-
firmed the solution based stoichiometry and proved that the
crystallisation process resulted in a diastereoselectivity in the
product, with di-p-toluoyl-D-tartaric acid crystallizing solely as
Fig. 3 ORTEP plot of 1-D-DTT with ellipsoids at 50% probability.
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Fig. 4 Illustration of the linear hydrogen bond chain along the b-crystallographic axis in the X-ray structure of 1-D-DTT.
were observed to racemize in basic solution, this procedure D-DBT result in the same selectivity and is assumed to be S-1
was completed as quickly as possible, and samples were only although due to the experimental constraints to determine the
prepared directly before subsequent use. In each case, an oil of samples directly after preparation to avoid racemization and
similar appearance to the racemate was obtained, each giving decomposition, and the fact that samples could not be run
identical 1H NMR and ES mass spectra to the starting com- sequentially, there is unfortunately a degree of variation in the
pounds 1, 2 and 3 respectively (Fig. S13–16†), and given the data obtained.
necessity to work quickly, the extraction process was not opti-
For racemic compound 2, two well-resolved peaks were
mized. If the procedure was completed using either aqueous again not observed, although a variety of different tempera-
sodium bicarbonate, or triethylamine as the base, lower yields tures and eluent ratios (2-propanol in n-hexane) were explored.
were typically obtained.
However, the principle peak had a notable shoulder consistent
The chiral stationary phase HPLC studies on both the with the presence of the two enantiomers (Fig. 5b). The traces
racemic cathinones 1, 2 and 3 along side the materials for the products obtained from the crystalline tartrate salts
retrieved following co-crystallization with the aromatic tartrate gave narrower peaks with the two potentially separated enan-
salts were attempted with the best separation observed with tiomers having marginally different retention times
n-hexane and 2-propanol (98 : 2) on an OJ-H column. For com- (Fig. S18†). Possible variation in the data given the experi-
pound 1, while two peaks are observed, clear baseline separ- mental requirements is acknowledged however. Similarly for
ation could not be obtained (Fig. 5a). For the resolved compound 3, the result was not ideal (Fig. 5c) possessing a
enantiomers of 1, formed from the extraction of the D-DTT, long tail assigned as compound decomposition on the
D-DBT and L-DBT salts, only a single peak is observed under column. Again with no clear baseline separation, but the com-
similar conditions by HPLC, albeit being relatively broad pounds isolate from 3-D-DBT ad 3-L-DBT eluted with different
(Fig. S17†). Given that the absolute stereochemistry deter- retention times as single broad peaks indicating success in the
mined by crystallography within 1-D-DTT, is the S-form (S-1), it chiral separation (Fig. S19†).
appears that this elutes before R-1. A very similar result
Analysis of the optical rotation of each of the samples
obtained from 1-D-DBT suggests that the use of D-DTT and obtained from extraction from the co-crystallized products
proved problematic, which is unsurprising given the limit-
ations in the quantity of available material, and possible tar-
trate contamination in the materials obtained; the rotations
were unsurprisingly inconsistent in their magnitude. Signifi-
cantly, all the materials obtained following extraction for
D-DTT and D-DBT salts were observed to give positive rotations,
whilst the sample isolated following co-precipitation with
L-DBT resulted in samples with a negative rotation. CD spec-
troscopy proved to be more reliable however; for the samples
isolated from either D-DTT or D-DBT, a positive Cotton effect
was observed at approximately 240 nm, and an equal and
opposite effect for the samples realised by co-crystallisation
with L-DBT (Fig. 6 and S16†).
The relative stability of the isolated materials were investi-
Fig. 5 HPLC traces of (a) rac-1, (b) rac-2 and (c) rac-3 (CHIRACEL®
gated, with a sample of R-2 being left overnight in the spectro-
OJ-H HPLC column, 2% 2-propanol in n-hexane, 298 K).
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pH. This is within a timescale that would permit their differen-
tial effects to be evaluated in biological media.
Experimental
All reagents were obtained from Sigma-Aldrich and used as
obtained unless otherwise stated. 1H NMR and 13C NMR
spectra were recorded on either a Bruker AVX (300 MHz) or
Bruker AVX (400 MHz). Chemical shifts (δ ppm) are reported
relative to CDCl3 (δ = 7.26 ppm) or DMSO (δ = 2.50 ppm).
HPLC spectra were recorded on Agilent 1100 Series. CHIRAL-
CEL® OJ-H chiral column from Daicel Chemical Industries
was used and the eluent employed was 1 to 3% 2-propanol
(HPLC grade) in n-hexane (HPLC grade). CD spectra were
recorded on a Jasco J-815 spectrometer under N2 at 20 C and all
the samples for CD spectroscopy were dissolved in methanol.
Optical rotation was recorded on a Perkin Elmer 341 polarimeter.
The compounds ( )-N,N-dimethylcathinone (1) ( )-N,N-di-
methylcathinone (2) and ( )-2-(1-pyrrolidinyl)-propiophenone
(3) are subject to legislation under the UK Misuse of Drugs Act
1971. The materials reported here were prepared and used
under a Schedule 1: licence to produce, possess and supply
(Ref DH001/11) issued by the Department of Health, Social
Services and Public Safety (Northern Ireland) to SEJB and NCF.
Fig. 6 Circular dichroism spectra of (a) S-1 (blue) and (b) R-1 (red)
obtained following extraction from the salts of 1-D-DTT and 1-L-DBT
respectively (8 × 10−5 mol dm−3 in methanol 293 K).
meter to racemize, (20 hours at 20 °C) resulting in a half life of
approximately 13.6 hours assuming first order racemization
kinetics (k = 1.4 × 10−5 −1), whilst repeating the experiment at
s
40 °C resulted in the half life decreasing to just 4.6 h, with the
other compounds showing similar half lives determined at
40 °C (3.5 and 6.4 h for R-1 and R-3). There was however no
observed degradation of the crystalline tartaric salt co-crystals
over the period of 6 months.
Synthetic procedures
( )-2-Bromopropiophenone.24,31 Propiophenone (3.0 mL,
22.4 mmol) was dissolved in glacial acetic acid (63 mL).
Bromine (1.15 mL, 22.4 mmol) was added dropwise into the
flask and the reaction was stirred at room temperature for
Conclusions
The tertiary cathinones 1, 2 and 3 have been prepared in 22 h. Aqueous Na2SO3 (0.1 M, 50 mL) was added and the
reasonable yield and characterized using NMR and mass spec- mixture extracted with dichloromethane (3 × 35 mL). The
troscopy. Chiral stationary phase HPLC indicates that the two organic layer was washed with a saturated aqueous Na2CO3
enantiomers can be observed, but despite our best efforts, solution (100 mL) and dried with MgSO4 and concentrated
clear baseline separation could not be achieved. The co-crystal- under vacuum giving the product as a yellow oil, which was
lized aromatic tartaric acid salts appear to result in single used without further purification. Yield = 90%. 1H NMR
enantiomeric form, with basic sodium hydroxide solutions (CDCl3, 300 MHz): δH = 8.02 (2H, d, J = 7.4 Hz, ArH), 7.58 (1H,
encouraging a dynamic resolution probably via a keto–enol t, ArH), 7.47 (2H, t, J = 7.4 Hz, ArH), 5.30 (1H, q, J = 7.0 Hz,
tautomerism, with the identity of the enantiopure cathinone CHBrCH3), 1.90 (3H, d, J = 7.0 Hz, CHCH3); 13C NMR (CDCl3,
confirmed by X-ray crystallography. Significantly, the free non- 100 MHz): δC = 193.4, 134.0, 133.7, 128.9, 41.4, 20.1; m/z TOF
racemic amines could be obtained following basification and MS EI+: 211.9861 ([M79Br]+, theoretical = 211.9837), 132.0760
extraction and in methanol these appear to be reasonably ([C9H8O]+), 118.0514 ([C8H6O]+), 77.0400, ([C9H8O]+).
stable at room temperature permitting their identity to be
determined by HPLC and CD spectroscopy.
( )-N,N-Dimethylcathinone (1).37,54 Dimethylamine hydro-
chloride (297 mg, 3.65 mmol) and triethylamine (0.98 mL,
Given the increasing interest in these materials due to both 7.00 mmol) dissolved in dichloromethane (38 mL) were added
their legal status, and their biological activity, these results are to 2-bromopropiophenone (773 mg, 3.63 mmol) in dichloro-
of interest in a number of important areas of current research. methane (23.5 mL) and stirred at room temperature for 21 h.
For example, these materials are being used as “recreational” The aqueous layer was acidified with aqueous HCl solution
drugs, yet the potency of the two enantiomeric forms remains (0.1 M, 100 mL) and washed with dichloromethane (100 mL).
unknown. This study demonstrates that these two forms can The pH was then adjusted to 10 using an aqueous NaOH solu-
now be readily isolated by a dynamic resolution, and in the tion (0.5 M, 20 mL) and extracted into dichloromethane (2 ×
crystalline form they are sufficiently stable to be stored for 100 mL), dried with MgSO4 and concentrated under vacuum
long periods of time. The free amines themselves, whilst giving the product as a yellow oil. Yield = 511 mg, 80% yield.
subject to slow racemization in methanol, are reasonably per- 1H NMR (CDCl3, 300 MHz): δH = 8.07 (2H, d, J = 7.5 Hz, ArH),
sistent, and potentially show similar behavior at physiological 7.56 (1H, d, J = 7.5 Hz, ArH), 7.46 (2H, t, J = 7.5 Hz, ArH), 4.07
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(1H, q, J = 6.8 Hz, CHCH3), 2.32 (6H, s, N(CH3)2), 1.27 (3H, d, m/z TOF MS EI+: 741.3358 ([MH + 1]+, theoretical = 741.3387),
J = 6.8 Hz, CHCH3); 13C NMR (CDCl3, 100 MHz): δC = 199.8, 564.2187 ([MH]+, theoretical = 564.2234), 178.1153 ([MH −
135.2, 131.6, 127.6, 63.3, 40.3, 9.8; m/z TOF MS EI+: DTT]+, theoretical = 178.1232).
177.1222 ([M]+, theoretical = 177.1154), 133.0605 ([C9H9O]+),
S-N,N-Dimethylcathinone D-DBT salt (1-D-DBT) white crys-
105.0304 ([C7H5O]+), 77.0343 ([C6H5]+); HPLC retention time: tals, yield = 60%. 1H NMR (DMSO-D6, 400 MHz): δH = 8.02 (2H,
7.47 min and 7.88 min (OJ-H chiral column, 3% 2-propanol in d, J = 7.5 Hz, ArH), 7.98 (4H, d, J = 7.5 Hz, Benz), 7.71–7.66
n-hexane, 298 K).
(3H, m, ArH), 7.58–7.52 (6H, m, Benz), 4.71 (1H, br, CHCH3),
( )-N,N-diethylcathinone (2) was prepared according to the 2.47 (6H, s, N(CH3)2), 1.26 (3H, m, CHCH3)); m/z TOF MS EI+:
same procedure to 2-(N,N-dimethylamino)-propiophenone 536.2458 ([MH]+, theoretical 536.1921), 178.1098 ([MH −
using diethylamine hydrochloride (372 mg, 3.10 mmol), tri- DBT]+, theoretical = 178.1232).
ethylamine (0.95 mL, 6.86 mmol) and 2-bromopropiophenone
R-N,N-Dimethylcathinone L-DBT salt (1-L-DBT) white crys-
(811 mg, 2.99 mmol) as a yellow oil. Yield = 395 mg, 62%. H tals, yield = 54%. 1H NMR (DMSO-D6, 400 MHz): δH = 8.02 (2H,
NMR (CDCl3, 300 MHz): δH = 8.10 (2H, d, J = 7.5 Hz, ArH), 7.53 d, J = 7.5 Hz, ArH), 7.98 (4H, d, J = 7.5 Hz, Benz), 7.71–7.66
(1H, t, J = 7.5 Hz, ArH), 7.43 (2H, t, J = 7.5 Hz, ArH), 4.37 (1H, (3H, m, ArH), 7.58–7.52 (6H, m, Benz), 4.70 (1H, br, CHCH3),
q, J = 6.7 Hz, CHCH3), 2.59–2.47 (4H, m, N(CH2CH3)2), 1.23 2.45 (6H, s, N(CH3)2), 1.26 (3H, t, J = 6.7 Hz, CHCH3); m/z TOF
(3H, d, J = 6.7 Hz, CHCH3), 1.01 (6H, t, J = 7.1 Hz, MS EI+: 536.3618 ([MH]+, theoretical = 536.1921), 178.1176
N(CH2CH3)2); 13C NMR (CDCl3, 100 MHz): δC = 202.20, 136.83, ([MH − DBT]+, theoretical = 178.1232).
1
132.52, 129.00, 60.44, 44.14, 13.61, 10.10; m/z TOF MS EI+:
S-N,N-Diethylcathinone D-DTT salt (2-D-DTT) yellow precipi-
205.1454 ([M]+, theoretical = 205.1467), 133.0589 ([C9H9O]+), tate, yield = 78%. 1H NMR (DMSO-D6, 400 MHz): δH = 8.05
100.1049 ([C6H14N]+), 77.0332 ([C6H5]+); HPLC retention time: (2H, d, J = 7.8 Hz, ArH), 7.85 (4H, d, J = 8.1 Hz, Tol), 7.66 (1H,
7.43 min, 7.74 min (OJ-H chiral column, 3% 2-propanol in t, J = 7.5 Hz, ArH), 7.54 (2H, dd, J = 7.8, 7.5 Hz, ArH), 7.35 (4H,
n-hexane, 298 K).
d, J = 8.1 Hz, ArH), 4.75 (1H, q, J = 6.9 Hz, CHCH3), 2.88–2.68
( )-2-(1-pyrrolidinyl)-propiophenone (3) was prepared (4H, m, N(CH2CH3)2), 2.37 (6H, s, TolCH3), 1.24 (3H, d, J =
according to the same procedure to 2-(N,N-dimethylamino)- 6.9 Hz, CHCH3), 1.06 (6H, t, J = 6.9 Hz, N(CH2CH3)2); m/z TOF
propiophenone using pyrrolidine (0.30 mL, 3.65 mmol) and MS EI+: 796.2039 ([MH + 2]+, theoretical = 796.3935), 206.1425
2-bromopropiophenone (942 mg, 4.44 mmol) as a brown oil. ([MH − DTT]+, theoretical = 206.1545).
Yield = 481 mg, 65%. 1H NMR (CDCl3, 300 MHz): δH = 8.11
S-N,N-Diethylcathinone D-DBT salt (2-D-DBT), yellow pre-
1
(2H, d, J = 7.5 Hz, ArH), 7.56 (1H, t, J = 7.5 Hz, ArH), 7.46 (2H, cipitate, yield = 85%. H NMR (DMSO-D6, 400 MHz): δH = 8.05
t, J = 7.5 Hz, ArH), 3.98 (1H, q, J = 6.9 Hz, CHCH3), 2.66–2.59 (2H, d, J = 7.6 Hz, ArH), 7.98 (4H, d, J = 7.7 Hz, Benz),
(4H, m, NCH2CH2), 1.83–1.77 (4H, m, CH2CH2–), 1.39 (3H, d, 7.72–7.64 (3H, m, ArH), 7.58–7.52 (6H, m, Benz), 4.85 (1H, br,
J = 6.9 Hz, CHCH3); 13C NMR (CDCl3, 100 MHz): δC = 202.20, CHCH3), 2.83–2.72 (4H, br, N(CH2CH3)2), 1.24 (3H, d, J =
136.83, 132.52, 129.00, 60.44, 44.14, 13.61, 10.10; m/z TOF MS 6.4 Hz, CHCH3), 1.05 (6H, t, J = 6.9 Hz, N(CH2CH3)2); m/z TOF
EI+: 203.1328 ([M]+, theoretical 203.1310), 98.0943 ([C6H12N]+) MS EI+: 769.4525 ([MH + 2]+, theoretical = 769.3700), 564.2867
77.0354 ([C6H5]+), 68.0471, ([C4H8N]+); HPLC retention time: ([M]+, theoretical 564.2233), 206.1601 206.1425 ([MH − DBT]+,
11.45 min, 11.89 min (OJ-H chiral column, 3% 2-propanol in theoretical = 206.1545).
n-hexane, 298 K).
R-N,N-Diethylcathinone L-DBT salt (2-L-DBT) off white pre-
1
(+)-O,O′-di-p-Toluoyl-D-tartaric, (+)-O,O′-dibenzoyl-D-tartaric cipitate, yield = 24%. H NMR (DMSO-D6, 400 MHz): δH = 8.06
(D-DTT), (+)-O,O′-dibenzoyl-L-tartaric (L-DBT) and (−)-O,O′- (2H, d, J = 7.5 Hz, ArH), 7.98 (4H, d, J = 7.6 Hz, Benz),
dibenzoyl-L-tartaric (L-DBT) acid salts of N,N-dimethyl- 7.72–7.64 (3H, m, ArH), 7.58–7.52 (6H, m, Benz), 4.83(1H, br,
cathinone (1), N,N-dimethylcathinone (2) and 2-(1-pyrrolidi- CHCH3), 2.83–2.72 (4H, br, N(CH2CH3)2), 1.25 (3H, d, J = 6.3
nyl)-propiophenone (3). In a typical procedure, compound 1, 2 Hz, CHCH3), 1.06 (6H, d, J = 6.8 Hz, N(CH2CH3)2); m/z TOF MS
or 3 (in the range of 0.5 mmol to 4.0 mmol depending on avail- EI+: 769.3741 ([MH + 2]+, theoretical = 769.3700), 564.2441
ability) was dissolved in acetone (approx. 0.1 M), the appropri- ([M]+, theoretical 564.2233), 206.1317 206.1425 ([MH − DBT]+,
ate tartaric acid (one equivalent relative to the cathinone) in theoretical = 206.1545).
water (approx. 0.1 M) and aqueous NaOH solution (0.1 M, one
S-2-(1-Pyrrolidinyl)-propiophenone D-DTT salt (3-D-DTT),
1
equivalent relative to the cathinone) were left to crystallize at white precipitate, yield = 22%. H NMR (DMSO-D6, 400 MHz):
room temperature in a loosely covered beaker over the period δH = 8.03 (2H, d, J = 7.9 Hz, ArH), 7.84 (4H, d, J = 8.1 Hz, Tol),
of several days. The resulting crystals/precipitates were col- 7.72 (1H, t, J = 7.5 Hz, ArH), 7.59 (2H, dd, J = 7.5, 7.9 Hz, ArH),
lected by filtration, washed with a little distilled water and 7.32 (4H, t, J = 8.1 Hz, Tol), 4.98 (1H, q, J = 6.3 Hz, CHCH3),
dried at room temperature.
3.11–3.02 (4H, m, NCH2CH2), 2.37 (6H, s, TolMe), 1.89–1.80
S-N,N-Dimethylcathinone D-DTT salt (1-D-DT) large white (4H, m, CH2CH2), 1.39 (3H, d, J = 6.3 Hz, CHCH3); m/z TOF MS
1
crystals, yield = 68%. H NMR (DMSO-D6, 400 MHz): δH = 8.02 EI+: 793.3068 ([MH + 3]+, theoretical = 793.3700), 590.1918
(2H, d, J = 8.0 Hz, ArH), 7.85 (4H, d, J = 8.1 Hz, Tol), 7.68 (1H, ([M]+, theoretical = 590.2390), 204.1028 ([MH − DTT]+, theore-
t, J = 7.3 Hz, ArH), 7.56 (2H, dd, J = 7.3, 8.0 Hz, ArH), 7.35 (4H, tical = 204.1388).
d, J = 8.1 Hz, Tol), 4.69 (1H, q, J = 6.7 Hz, CHCH3), 2.45 (6H, s,
S-2-(1-Pyrrolidinyl)-propiophenone D-DBT salt (3-D-DBT),
TolCH3), 2.38 (6H, s, N(CH3)2), 1.25 (3H, d, J = 6.7 Hz, CHCH3); pale orange precipitate, yield = 53%. 1H NMR (DMSO-D6,
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400 MHz): δH = 8.02 (2H, d, J = 7.5 Hz, ArH), 7.96 (4H, d, J = CrystalClear-SM Expert 3.1 b27.58 Structure solution was per-
7.8 Hz, Benz), 7.72 (1H, t, J = 7.5 Hz, ArH), 7.66 (2H, t, J = formed using SUPERFLIP59 and the Structure refinement using
7.5 Hz, ArH), 7.59 (2H, t, J = 7.8 Hz, Benz), 7.52 (4H, t, J = 7.8 SHELXL-2015.60 Graphics were prepared using ORTEP3 for
Hz, Benz), 5.00 (1H, br, CHCH3), 3.12–3.03 (4H, br, NCH2CH2), Windows61 and Mercury 3.5.1.62 Additional material available
1.85–1.77 (4H, m, CH2CH2), 1.37 (3H, d, J = 6.7 Hz, CHCH3); from the Cambridge Crystallographic Data Centre comprises
m/z TOF MS EI+: 765.3441 ([MH + 3]+, theoretical = 765.3387), relevant tables of atomic coordinates, bond lengths and
562.2391 ([M]+, theoretical 562.2077), 204.1170 ([MH − DBT]+, angles, and thermal parameters (CCDC number 1407691). It
theoretical = 204.1388).
was not possible to accurately determine the absolute con-
R-2-(1-Pyrrolidinyl)-propiophenone L-DBT salt (3-L-DBT) figuration; the enantiomer has been assigned by reference to
orange precipitate, yield = 61%. 1H NMR (DMSO-D6, 400 MHz): the absolute configuration of (+)-O,O′-di-p-toluoyl-D-tartaric
δH = 8.04 (2H, d, J = 7.5 Hz, ArH), 7.95 (4H, d, J = 7.8 Hz, Benz), acid. C31H33F12NO9: M = 563.58, monoclinic, space group P21,
7.73 (1H, t, J = 7.5 Hz, ArH), 7.65 (2H, t, J = 7.5 Hz, ArH), 7.59 a = 8.2681(5) Å, b = 7.5543(5) Å, c = 23.4201(17) Å, β = 96.148(3)°,
(2H, t, J = 7.8 Hz, Benz), 7.52 (4H, t, J = 7.8 Hz, Benz), 5.00 (1H, vol = 1454.40(17) Å3, Z = 2, absorb. coef. = 0.095 mm−1, a total
br, CHCH3), 3.12–3.03 (4H, br, NCH2CH2), 1.85–1.77 (4H, m, of 13 021 reflections were measured for the angle range
CH2CH2), 1.37 (3H, d, J = 6.7 Hz, CHCH3); m/z TOF MS EI+: 2.478–27.514°, 6380 [Rint = 0.0994] independent reflections
765.3456 ([MH + 3]+, theoretical = 765.3387), 562.2148 ([M]+, were used in the refinement. The final R indices [F2 > 2σ(F2)]]
theoretical = 562.2077), 204.1349 ([MH − DBT]+, theoretical = were R1 = 0.0865, wR2 = 0.1920, and a GOF on F2 at 1.037.
204.1388).
Conversion of the tartaric acid salts to the non-racemic-free
amines
Acknowledgements
In a typical procedure, the tartrate salts (20 mg, approx. This work was principally funded by Queen’s University
0.10 mmol) were dissolved in aqueous sodium hydroxide solu- Belfast. We thank the involvement of both the Forensic Service
tion (0.1 M, 15mL). The mixture was extracted by dichloro- of Northern Ireland, and the Department of Health, Social Ser-
methane (20 mL) and the organic layer dried with MgSO4 and vices and Public Safety, Northern Ireland (Prof. Mike
concentrated under vacuum to give a yellow oil in a range of Mawhinney).
yields between 56 and 83%. 1H, 13C NMR and OF MS EI+
characterization of samples was in accordance with that of the
racemic mixtures of 1, 2 and 3.
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