Synthesis of 2-Arylethylamines by the Curtius Rearrangement

Article abstract of DOI:10.1080/00397910903097302

2-Arylethylamine derivatives were synthesized using the Curtius reaction and with three different methods of preparing the acyl azide functional group. Carbamates derived from isocyanate were convenient protecting groups for alkylation of amines. Starting from benzaldehyde, amphetamine was prepared in three steps through an oxazolidin-2-one intermediate in 62% overall yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903097302

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Synthesis of 2-Arylethylamines by the
Curtius Rearrangement
Matthias Schulze a
a Department of Pharmacology and Toxicology, College of Pharmacy,
University of Arizona, Tucson, Arizona, USA
Version of record first published: 23 Apr 2010.
To cite this article: Matthias Schulze (2010): Synthesis of 2-Arylethylamines by the Curtius
Rearrangement, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:10, 1461-1476
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Synthetic Communications1, 40: 1461–1476, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903097302
SYNTHESIS OF 2-ARYLETHYLAMINES BY THE
CURTIUS REARRANGEMENT
Matthias Schulze
Department of Pharmacology and Toxicology, College of Pharmacy,
University of Arizona, Tucson, Arizona, USA
2-Arylethylamine derivatives were synthesized using the Curtius reaction and with three
different methods of preparing the acyl azide functional group. Carbamates derived from iso-
cyanate were convenient protecting groups for alkylation of amines. Starting from benzal-
dehyde, amphetamine was prepared in three steps through an oxazolidin-2-one
intermediate in 62% overall yield.
Keywords: Curtius rearrangement; isocyanate; oxazolidin-2-one; potassium tert-butoxide
Some of the major neurotransmitters in the vertebrate central nervous system are
derivatives of 2-arylethylamines (Chart 1). Chemicals that can penetrate the nervous
system tissue may have profound effects on the behavior of an organism. Four struc-
tural analogs (1–4) of dopamine are shown in Chart 2, including amphetamine (1),
methamphetamine (2), 3,4-methylendioxymethamphetamine (3) and mescaline (4).
This report describes the novel chemical synthesis of compounds 1–4 as part of a
project to study the in vitro binding assays of these analogs at various dopamine,
serotonin, and norepinephrine receptors.
The route developed for the synthesis of 1 and 2 is shown in Scheme 1. Using
conditions similar to those employed by Moersch and others,[1–7] we reacted benzal-
dehyde with the dilithium dianion of propionic acid at an ice-bath temperature to get
b-hydroxycarboxylic acid 5 in a 42:58 erythro=threo diastereomeric ratio based on
proton nuclear magnetic resonance (NMR) spectroscopy.[8] This ratio remained
approximately the same over the next steps, and no attempt was made to separate
this or the following mixtures (6,7) because one chiral center would eventually be
eliminated. It was convenient to have several NMR studies on the diastereomers
of 6 and 7.[9–11] Curtius rearrangement of 5 by diphenylphosphoryl azide (DPPA)[12]
in the presence of triethylamine in refluxing toluene gave the oxazolidin-2-one mix-
ture 6 in excellent yield.[8,13,14] Effenberger and Ja¨ger[15] noticed that these
5-aryloxazolidin-2-ones contain an intramolecular cyclized carbobenzyloxy (Cbz)
protecting group of the nitrogen atom. As such, these compounds are readily
Received April 15, 2009.
Address correspondence to Matthias Schulze, Department of Pharmacology and Toxicology,
College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA. E-mail: mcschulze70@gmail.com
1461

1462
M. SCHULZE
Chart 1. Neurotransmitters.
Chart 2. 2-Arylethylamines synthesized.
deprotected by catalytic hydrogenation, which reduces the benzylic position to CH2
and yields the free 2-arylethylamines. To finish the preparation of racemic 1,
catalytic hydrogenation of 6 gave the free base, which was isolated and precipitated
as its hemioxalate salt. Because the N-H acidity (pKa) of carbamate in dimethylsulf-
oxide has been measured between 21 and 24,[16] it is possible to deprotonate it with
strong nonhydride-type bases such as potassium tert-butoxide.[17–19] Reaction of 6
with iodomethane in tetrahydrofuran in the presence of this base gave the N-methyl
mixture 7 in excellent yield. This mixture was a distillable oil, although each pure
diastereomer is a solid at room temperature (51 and 91 ꢀC).[9,20–22] Subsequent
Scheme 1. Synthesis of 1, 2, and 8. Reagents and conditions: (a) CH3CH2CO2H, LDA, THF, 0 ꢀC; (b)
DPPA, PhMe, reflux; (c) KOtBu, THF; (d) 1. H2, 5% Pd=C, EtOH; 2. (CO2H)2, EtOH; (e) KOH,
H2O, EtOH, reflux.

SYNTHESIS OF 2-ARYLETHYLAMINES BY THE CURTIUS REARRANGEMENT 1463
catalytic hydrogenation of 7 gave the racemic N-methyl derivative 2, which was iso-
lated and precipitated as its oxalate salt. To demonstrate further utility of the syn-
thetic route, 7 was hydrolyzed with potassium hydroxide in aqueous ethanol to
give a mixture of ephedrine and pseudoephedrine.
A different synthetic route was adopted for the synthesis of 3 (Scheme 2).
Starting from commercially available heliotropin (2), the Perkin reaction using con-
ditions of Mann and Woolf[23] gave the cinnamic acid derivative 9.[24–30] It was not
necessary to carry out an elaborate acid=base extraction process because crude 9
precipitated from the aqueous workup. In the next step, catalytic hydrogenation
of 9 in tetrahydrofuran gave the racemic propionic acid derivative 11.[26] An alter-
nate route to 11 was by oxidation of the commercially available fragrance additive
2-methyl-3-(3,4-methylenedioxyphenyl)propanal[31–33](10) with potassium peroxy-
monosulfate (Oxone) in N,N-dimethylformamide (DMF).[34]
When a mixture of 11, DPPA, and triethylamine in ethanol was refluxed, an
excellent yield of the corresponding ethylcarbamate was obtained (data not shown).
However, running the same reaction with tert-butanol as solvent failed to yield the
analogous tert-butyloxycarbonyl (Boc)–protected amine (15). Instead, a fair yield of
a solid was obtained, which appeared by proton NMR spectroscopy to be the cor-
responding urea. This is reminiscent of the results of Jones and Wallis,[35] who found
that simply heating the desmethylenedioxy analog of 14 in water gave a quantitative
yield of the symmetrical urea.[36] A literature survey found mixed results in the
reaction of isocyanates and alcohols that are both sterically hindered.[37–41]
Continuing in a more linear fashion, the acid 11 was readily converted into the
acid chloride 12 by stirring at room temperature with thionyl chloride. Reaction of
Scheme 2. Synthesis of MDMA. Reagents and conditions: (a) CH3CH2CO2Na, (CH3CH2CO)2O, reflux;
(b) H2, 5% Pd=C, THF; (c) oxone, DMF; (d) SOCl2; (e) NaN3, H2O, DCE; (f) 60 ꢀC, DCE; (g) KOtBu,
HOtBu, THF; (h) MeI, KOtBu, THF; (i) conc. HCl, THF, 45 ꢀC; (j) (CO2H)2, EtOH.

1464
M. SCHULZE
12 with sodium azide in a biphasic mixture of 1,2-dichloroethane and water at ice-bath
temperature gave the acyl azide 13. The latter derivative was not isolated but, after dry-
ing its solution in 1,2-dichloroethane, was gently heated to bring about rearrangement
to isocyanate 14 in 91% yield over the two steps. With the isocyanate in hand, Boc pro-
tection of the amine was chosen because it is easily removed. Following the lesson from
the DPPA=tert-butanol reaction, the more nucleophilic KOtBu was reacted with 14 in
tetrahydrofuran (THF) to obtain carbamate 15 as a crystalline solid.[42–44]
Typically, carbamates such as 15 can be reduced with hydride reagents such as
lithium tetrahydroaluminate to give an N-methylated amines.[45,46] Instead, follow-
ing the strategy of Trachsel et al.,[47] 15 was methylated with iodomethane and
KOtBu in dimethylformamide to give 16 in excellent yield. It is interesting to note
that Tom et al.[48] used sodium tert-butoxide to efficiently remove Boc protection
from primary amines.
It was anticipated that 16 would also be a solid at room temperature but was a
distillable liquid. This is probably a result of 16 existing as a mixture of rotamers
about the N-carbonyl bond.[49–55] As shown in Fig. 1, the proton NMR spectrum
of 16 in deuteriomethylsulfoxide at room temperature (26 ꢀC) had broad peaks
across the aliphatic region. The a-CH (ꢁ4.25 ppm) appears as two overlapping
broad peaks as well as both the t-butyl (ꢁ1.25 ppm) and a-methyl (ꢁ1.05 ppm)
groups. When the sample was heated (76 ꢀC) in the probe, the resonances became
much sharper as there is free rotation about the amide bond. In addition, the 13C
NMR spectrum of 16 at room temperature shows two extra peaks for both the
a-CH and N-CH3 (see Experimental) that also each coalesce to single peaks when
heated (data not shown).
Finally, there are several methods for the removal of Boc-protected amines such
as trifluoroacetic acid, methanesulfonic acid, or dry hydrogen chloride in organic sol-
vent.[56] Deprotection of 16 to racemic free base 3 was readily achieved in nearly quan-
titative yield by reaction with concentrated hydrochloric acid in warm THF.[57–60] For
storage and handling convenience, amine 3 was converted into its oxalate salt.
Figure 1. Variable temperature 1H-NMR study of carbamate 16 in DMSO-d6.

SYNTHESIS OF 2-ARYLETHYLAMINES BY THE CURTIUS REARRANGEMENT 1465
Scheme 3. Synthesis of mescaline salts. Reagents and conditions: (a) 1. ClCO2Et, TEA, DCE; 2. NaN3,
H2O; 3. reflux; (b) H2O, 0.5 equiv or excess conc. H2SO4, 80 ꢀC.
The starting material for the synthesis of 4[61–63] was commercially available 17
(Scheme 3).[62,64] Several attempts to isolate the acid chloride of 17 from reaction
with thionyl chloride failed. Instead, the mixed carboxylic–carbonic anhydride
method of Weinstock[65,66] was used to synthesize the acyl azide of 17 in situ. To elim-
inate possible formation of the anhydride of 17, a solution of 17 and triethylamine
was added to the solution of ethyl chloroformate.[67,68] 1,2-Dichloroethane was an
excellent choice of solvent as the triethylamine hydrochloride by-product precipitated
virtually quantitatively. By proton NMR, there was a characteristic upfield shift of
the quartet of the CH2 group in ethyl chloroformate from 4.4 to 4.2 ppm, indicating
formation of the mixed carboxylic–carbonic anhydride. To generate the acyl azide, an
aqueous solution of sodium azide was added to the reaction mixture. Thin-layer chro-
matography (TLC) was convenient to diagnose reaction progress. By proton NMR
analysis, the disappearance of the quartet at 4.2 ppm of the mixed carboxylic–car-
bonic anhydride was indicative of acyl azide formation, and all the other resonances
remained unchanged. After washing and drying the 1,2-dichloroethane solution of
the acyl azide, refluxing the solution brought about the Curtius rearrangement. The
isocyanate 18[69–71] was found to be a distillable, low-melting solid.
Because alkylation of the amine of target 4 was unnecessary, 18 was hydrolyzed in
aqueous acid. Heating 18 in water with one-half equivalent or excess sulfuric acid caused
evolution of carbon dioxide and gave the hemisulfate or sulfate of 4, respectively.[61,72]
Fortunately, these hydrolyses were not complicated by sulfamic acid formation.[73]
In conclusion, the Curtius rearrangement was an effective method to install the
nitrogen atom of 2-arylethylamine derivatives. Carbamate protection of the amines
allowed for the clean alkylation of a primary amine. These routes avoid the use of
hazardous metal and metal hydride reagents typically employed in the synthesis of
this class of pharmacologic agents.
EXPERIMENTAL
Melting points were collected on an electrothermal capillary melting-point
apparatus and are not corrected. Nuclear magnetic resonance (NMR) spectroscopy
was performed on a Bruker Avance 300-MHz (1H, 300 MHz; 13C, 75 MHz)
instrument. All samples were referenced to tetramethylsilane (TMS) as internal

1466
M. SCHULZE
standard or solvent. Heliotropin (2) 99%, sodium propionate 99%, propionic
anhydride 97%, iodomethane 99%, thionyl chloride (SOCl2) 97%, sodium azide
99%, tert-butanol (tBuOH) 99%, potassium tert-butoxide (KOtBu) 95%, anhydrous
dimethylformamide (DMF) 99.8%, diphenylphosphoryl azide (DPPA) 97%, tetrabu-
tylammonium bromide (TBAB) 98%, 1,2-dichloroethane (DCE) 99%, anhydrous
THF 99% (inhibited with 250 ppm 2,6-di-tert-butyl-4-methylphenol), oxalic acid
dihydrate 99%, 2.3 M hexyllithium in hexanes, anhydrous diisopropylamine (DIPA),
5% palladium on carbon (Pd=C), Oxone monopersulfate compound, and 2-methyl-
3-(3,4-methylenedioxyphenyl)-propanal (10, Chemical Abstracts Service Registry
Number 1205-17-0) were purchased from Sigma-Aldrich (Milwaukee). All other
reagents were obtained commercially and used as received. Elemental analyses were
performed by Atlantic Microlab, Inc. (Norcross, GA).
2-Methyl-3-hydroxy-3-phenylpropionic Acid (5) Mixture of
Diastereomers
A 500-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 150 mL THF and 33 mL DIPA (0.23 mol). A 250-mL addition funnel was
attached, and the apparatus was protected with an N2 bubbler. The mixture was stir-
red in an ice bath. Once cold, the addition funnel was charged with 100 mL 2.3 M hex-
yllithium in hexanes (0.23 mol), which were then added in a gentle stream over 20 min.
A new addition funnel was equipped and charged with 6.9 mL propionic acid
(0.276 mol, 1.2 equiv), which was added dropwise over 15 min. Copious solids preci-
pitated during the addition. The reaction was stirred in a 50 ꢀC bath for 45 min and
then cooled in an ice bath once again. A new addition funnel was equipped and
charged with 7.8 mL benzaldehyde (0.23 mol), which was added dropwise over
15 min. The cooling bath was removed, and the mixture was stirred at rt for 3 h. A
solution of 200 mL 7.5% NaOH was added, and the mixture was stirred for 10 min.
The aqueous layer was separated and acidified to pH 3 with 120 mL 6 M HCl and
extracted with Et2O (four times, 100 mL). The combined extracts were washed with
100 mL brine and then dried over anhydrous MgSO4. Evaporation of the solvent
and some residual propionic acid left 9.5 g of a colorless oil (68%). Agitation with
100 mL of 10% Et2O in hexanes caused the oil to solidify, yielding a white crystalline
solid. Mp 64–68 ꢀC. dH (DMSO): 12.13 (bs, 2 CO2H), 7.46–7.15 (m, 10H), 5.43 (bs, 2
OH), 4.87 (d, J ¼ 5.8 Hz, 1H, erythro), 4.62 (d, J ¼ 9.0 Hz, 1H, threo), 2.67–2.53
(overlapping pentets, 2H), 1.02 (d, J ¼ 6.8 Hz, 1H, threo), 0.77 (d, J ¼ 7.0 Hz, 1H, ery-
thro); dC (DMSO): 176.16, 175.43, 144.21, 143.25, 128.02, 127.87, 127.32, 126.93,
126.83, 126.24, 75.09, 73.22, 47.48, 47.00, 13.66, 11.67. Elemental analysis calculated
for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.47; H, 6.70.
4-Methyl-5-phenyloxazolidin-2-one (6) Mixture of Diastereomers
A 500-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 50 mL toluene, 4.7 g TEA (46.6 mmol, 1.2 equiv), and 7 g 5 (39 mmol). The mix-
ture was stirred at rt while 12.8 g DPPA (46.6 mmol, 1.2 equiv) was added dropwise
over 5 min. The mixture was then stirred at 55 ꢀC, and gentle evolution of N2
occurred. After stirring overnight at this temperature, the mixture was cooled to

SYNTHESIS OF 2-ARYLETHYLAMINES BY THE CURTIUS REARRANGEMENT 1467
rt, and 50 mL saturated aqueous NaHCO3 were added along with 50 mL EtOAc.
The phases were separated, and the organic layer was further washed with 50 mL
1 M HCl followed by 50 mL H2O and then 50 mL brine. The organic layer was dried
over anhydrous MgSO4 and rotary evaporated, leaving a crude white solid. The
crude was slurried with 50 mL hexanes and filtered on a medium glass frit to give
6.27 g of white solid (91%). 1H NMR shows the product is a mixture of cis=trans dia-
stereomers. dH (CDCl3): 7.46–7.20 (m, 10H), 6.22 (bs, NH, cis), 6.13 (bs, NH, trans),
5.71 (d, J ¼ 7.9 Hz, 1H, trans), 5.04 (d, J ¼ 7.3 Hz, 1H, cis), 4.20 (pent, J ¼ 7.3 Hz,
1H, trans), 3.84 (pent, J ¼ 6.1 Hz, 1H, cis), 1.39 (d, J ¼ 6.1 Hz, 3H, cis), 0.81 (d,
J ¼ 6.7 Hz, 3H, trans); dC (CDCl3): 159.87, 159.45, 137.94, 135.18, 129.16, 129.05,
128.68, 128.64, 126.16, 126.09, 85.59, 81.21, 56.75, 52.61, 20.13, 17.65. Elemental
analysis calculated for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.38;
H, 6.24; N, 7.86.
a-Methyl-2-phenylethylamine (1) Hemioxalate
A 100-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 1.07 g 5 (6 mmol), 100 mg 5% Pd=C, and 20 mL anhydrous THF. The mixture
was hydrogenated (ꢁ1 torr, rt) for 3 h. The mixture was filtered through celite and
rotary evaporated, leaving 800 mg of a colorless oil of 1 (100%). [dH (CDCl3):
7.34–7.14 (m, 5H), 3.16 (hex, J ¼ 6.4 Hz, 1H), 2.70 (dd, J ¼ 13.3 and 5.5 Hz, 1H),
2.52 (dd, J ¼ 13.3 and 8.0 Hz, 1H), 1.46 (bs, NH2), 1.11 (d, J ¼ 6.2 Hz, 3H); dC
(CDCl3): 139.84, 129.42, 128.55, 126.35, 48.67, 46.79, 23.64]. An EtOH solution of
the amine was added dropwise to a stirred mixture of 378 mg oxalic acid dihydrate
(3 mmol, 0.5 equiv) dissolved in EtOH. The white precipitate was collected and air
dried on the frit; no further purification was necessary. Mp 140 ꢀC (shrank),
190 ꢀC (dec.). dH (D2O): 7.45–7.25 (m, 5H), 3.59 (hex, J ¼ 6.9 Hz, 1H), 2.91 (dd,
J ¼ 7.4 and 2.3 Hz, 2H), 1.27 (d, J ¼ 6.4 Hz, 3H); dC (D2O): 160.66, 128.13, 121.41,
120.97, 119.34, 41.03, 32.04, 9.44. Elemental analysis calculated for C9H13N ꢂ 0.5
C2H2O4: C, 66.64; H, 7.83; N, 7.77. Found: C, 66.51; H, 7.79; N, 7.71.
3,4-Dimethyl-5-phenyloxazolidin-2-one (7) Mixture of Diastereomers
A 100-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 50 mL THF and 4.71 g 6 (0.027 mol), and the mixture was stirred in an ice bath.
In one portion, 4.47 g KOtBu (0.04 mol, 1.5 equiv) were added, and the mixture was
stirred for 15 min. In one portion, 7.53 g iodomethane (3.3 mL, 0.05 mol, 2 equiv)
were added, and the cooling bath was removed. Shortly thereafter, a precipitate of
KI formed. After stirring at rt for 1 h, 100 mL H2O and 100 mL Et2O were added.
The organic layer was separated, washed with brine, and then dried over anhydrous
MgSO4. Evaporation of the solvent left 4.78 g of a pale yellow oil (94%) that was
1
>97% by H NMR. The oil would not crystallize even after overnight vacuum or
cooling to ꢃ20 ꢀC. The oil was distilled (0.1 torr) to give the title compound as a
nearly colorless oil composed of a cis=trans mixture of diastereomers. dH (CDCl3):
7.46–7.24 (m, 10H), 5.59 (d, J ¼ 8.2 Hz, 1H, trans), 4.91 (d, J ¼ 8.2 Hz, 1H), 4.03
(pent, J ¼ 6.1 Hz, 1H, trans), 3.55 (pent, J ¼ 6.1 Hz, 1H, cis), 2.87 (s, 3H, trans),
2.85 (s, 3H, cis), 1.37 (d, J ¼ 6.1 Hz, 3H, cis), 0.79 (d, J ¼ 6.5 Hz, 3H, trans);

1468
M. SCHULZE
dC (CDCl3): 158.11, 157.86, 137.79, 135.35, 129.02, 128.93, 128.54, 125.51, 126.23,
126.01, 82.52, 78.42, 61.34, 57.12, 29.02, 28.83, 17.40, 14.31. Elemental analysis cal-
culated for C11H13NO2: C, 69.09; H, 7.01; N, 7.33. Found: C, 69.14; H, 7.01; N, 7.33.
N,a-Dimethyl-2-phenylethylamine (2) Oxalate
A mixture of 4.3 g 7 (0.02 mol) and 100 mg 5% Pd=C in 20 mL EtOH was
hydrogenated at near atmospheric pressure overnight. The catalyst was filtered away
through Celite, and the solvent was evaporated, leaving a 2.98 g of a colorless oil of 2
1
that was more than 97% by H NMR (100%). dH (CDCl3): 7.34–7.16 (m, 5H),
2.89–2.72 (m, 2H), 2.67–2.49 (m, 2H), 2.42 (s, 3H), 1.08 (d, J ¼ 6.1 Hz, 3H); dC
(CDCl3): 139.47, 129.51, 128.62, 126.43, 56.56, 43.34, 33.83, 19.56. A solution of
2.52 g oxalic acid dihydrate (0.02 mol, 1 equiv) in 25 mL EtOH was stirred, and a
solution of the amine in 5 mL EtOH was added. After stirring for 30 min, the salt
precipitated and was filtered on a coarse porosity glass frit. After air-drying on
the frit, 4.65 g of the title compound was obtained as a white microcrystalline powder
that was analytically pure (97%). Mp 149–151 ꢀC. dH (DMSO): 8.5–7.37 (bs, 3H),
7.37–7.19 (m, 5H), 3.42–3.26 (m, 1H), 3.17 (dd, J ¼ 12.6 and 3.7 Hz, 1H), 2.68–2.5
(m, 4H), 1.07 (d, J ¼ 6.3 Hz, 3H); dC (DMSO): 164.92, 136.89, 129.25, 128.57,
126.74, 55.19, 38.28, 29.67, 14.86. Elemental analysis calculated for
C10H15N ꢂ C2H2O4: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.21; H, 7.10; N, 5.82.
2-(Methylamino)-1-phenylpropan-1-ol (8) Mixture of Diastereomers
A mixture of 1.84 g 7 (9.6 mmol) in 23 mL 20% KOH in H2O and 23 mL EtOH
was refluxed. After 2 h, the mixture was poured into H2O and extracted three times
with 50-mL portions of Et2O. The organic phases were collected and washed with
25 mL brine and dried over anhydrous MgSO4. Evaporation of the solvent left
0.8 g of a white solid (50%). Mp 65–71 ꢀC. dH (CDCl3): 7.39–7.21 (m, 10H), 4.76
(d, J ¼ 4.0 Hz, 1H, erythro), 4.18 (d, J ¼ 8.2 Hz, 1H, threo), 2.81 (qd, J ¼ 6.6 and
4.0 Hz, 1H, erythro), 2.61 (dq, J ¼ 8.1 and 6.6 Hz, 1H, threo), 2.49 (s, 3H, erythro),
2.45 (s, 3H, threo), 0.94 (d, J ¼ 6.4 Hz, 3H, threo), 0.83 (d, J ¼ 6.4 Hz, 3H, erythro);
dC (CDCl3): 142.70, 141.97, 128.42, 128.26, 127.76, 127.19, 126.33, 77.83, 73.38,
61.48, 60.63, 34.14, 33.66, 15.78, 14.34. Elemental analysis calculated for
C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.44; H, 9.31; N, 8.57.
trans-3-(3,4-Methylenedioxyphenyl)-2-methylacrylic Acid (9)
A 1-L, round-bottomed flask equipped with magnetic stirbar and reflux con-
denser was charged with 62.2 g helional (0.415 mol), 39.8 g sodium propionate
(0.415 mol, 1 equiv), and 100.2 mL propionic anhydride (8 equiv). The mixture was
refluxed for 3 h. An aliquot of the reaction mixture was dissolved in deuteriomethyl-
sulfoxide, and 1H NMR showed all the aldehyde had been consumed. While hot, the
mixture was poured into 2 L H2O, causing a tan solid to precipitate. The solid was
collected on a coarse-porosity glass frit and air dried for several hours on the frit.
The solid was slurried with Et2O, filtered, washed with hexanes, and air-dried on
the frit to give 43.4 g of the product as an off-white powder (53%). The title compound

SYNTHESIS OF 2-ARYLETHYLAMINES BY THE CURTIUS REARRANGEMENT 1469
was obtained in analytically pure form by recrystallization from MeCN. Mp
195–197ꢀC. (lit.[26] 192–194 ꢀC). dH (DMSO): 7.51 (d, J ¼ 1.5 Hz, 1H), 7.06 (s, 1H),
6.97 (m, 2H), 6.06 (s, 2H), 2.01 (d, J ¼ 1.5 Hz, 3H); dC (DMSO): 169.62, 147.53,
147.51, 137.59, 129.65, 126.97, 124.63, 109.50, 108.45, 101.42, 14.02. Elemental analy-
sis calculated for C11H10O4: C, 64.07; H, 4.89; O, 31.04. Found: C, 64.15; H, 4.78.
Racemic 3-(3,4-Methylenedioxyphenyl)-2-methylpropionic Acid (11)
Method A from 9. A suspension of 43.4 g 9 (0.21 mol) and 1 g 5% Pd=C in
500 mL THF was hydrogenated on a Parr shaker at 40 psi for 3 h. After this time,
uptake of H2 ceased, and the mixture was filtered through Celite. The colorless
filtrate was rotary evaporated to an oil that slowly crystallized to an off-white solid
(41.05 g, 94%). Mp 72–74 ꢀC (lit.[26] 77 ꢀC). dH (CDCl3): 10.27 (bs, CO2H), 6.67 (d,
J ¼ 7.6 Hz, 1H), 6.62 (d, J ¼ 1.5 Hz, 1H), 6.57 (dd, J ¼ 7.6 and 1.9 Hz, 1H), 5.87 (s,
2H), 2.92 (dd, J ¼ 13.2 and 6.2 Hz, 1H), 2.64 (hextet, J ¼ 7.2 Hz, 1H), 2.54 (dd,
J ¼ 13.2 and 7.7, 1H), 1.11 (d, J ¼ 7.3 Hz, 3H); dC (CDCl3): 182.77, 147.80, 146.29,
132.96, 122.15, 109.51, 108.36, 101.07, 41.69, 39.21, 16.59. Elemental analysis calcu-
lated for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.59; H, 5.66.
Method B from 10. A 500-mL round-bottomed flask equipped with magnetic
stirbar was charged with 19.2 g 10 (16.55 mL, 0.1 mol) and 250 mL anhydrous DMF.
In one portion, 61.5 g Oxone (0.1 mol, 1 equiv.) was added, and the internal tempera-
ture peaked at 55 ꢀC and then cooled to rt over 1 h. After this time, TLC showed all
the starting aldehyde had been consumed, and the mixture was poured into 1 L H2O.
After stirring for several hours to allow precipitation, 17.42 g of title compound
was collected on a medium glass frit (84%). No further purification was necessary.
Spectroscopic data for the product were identical to that found from method A.
Racemic 3-(3,4-Methylenedioxyphenyl)-2-methylpropionyl
Chloride (12)
A suspension of 5 g 11 (0.24 mol) and 3.5 mL SOCl2 (2 equiv) was stirred under
N2 overnight. The resulting green solution was evaporated to remove the excess
SOCl2. A few milliliters of toluene were added, and this was distilled under reduced
pressure to chase away residual SOCl2, HCl, and SO2. The resulting oil was distilled
under reduced pressure (0.1 torr) to give 4.8 g of the title compound as a pale yellow
liquid (88%). The liquid may solidify on standing over several days. dH (CDCl3): 6.68
(d, J ¼ 7.8 Hz, 1H), 6.59 (d, J ¼ 1.5 Hz, 1H), 6.57 (dd, J ¼ 7.7 and 1.8 Hz, 1H), 5.87
(s, 2H), 3.01 (m, 2H), 2.62 (m, 1H), 1.21 (d, J ¼ 6.8 Hz, 3H); dC (CDCl3): 177.19,
148.01, 146.71, 131.39, 122.31, 109.48, 108.56, 101.21, 53.68, 39.17, 16.77. Elemental
analysis calculated for C11H11ClO3: C, 58.29; H, 4.89. Found: C, 58.56; H, 4.98.
Racemic 3-(3,4-Methylenedioxyphenyl)-2-propyl Isocyanate (14)
A 250-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 12.66 g 12 (55.8 mmol), 100 mg TBAB, and 150 mL DCE. The mixture was
cooled in an ice bath while a solution of 4.5 g NaN3 (69.8 mmol, 1.25 equiv) in

1470
M. SCHULZE
10 mL H2O was added dropwise over 30 min. The mixture was reacted at 5 ꢀC for 1 h.
After this time, 1H NMR showed all 6 had been consumed to give racemic
3-(3,4-methylenedioxyphenyl)-2-methylpropionyl azide (13) [dH (CDCl3): 6.73 (d,
J ¼ 7.9 Hz, 1H), 6.65 (d, J ¼ 1.6 Hz, 1H), 6.61 (dd, J ¼ 7.9 and 1.6 Hz, 1H), 5.93 (s,
2H), 2.95 (dd, J ¼ 12.5 and 6.6 Hz, 1H), 2.71–2.53 (m, 2H), 1.16 (d, J ¼ 6.6 Hz,
3H); dC (CDCl3): 183.49, 147.88, 146.40, 132.58, 122.13, 109.45, 108.43, 101.11,
44.09, 39.23, 16.76]. While keeping the organic phase at ice-bath temperature as
much as possible, the mixture was separated, and the organic phase was washed with
25 mL H2O followed by 50 mL brine. The organic layer was dried over 5 g anhydrous
MgSO4 and filtered into a 500-mL Erlenmeyer flask containing a magnetic stirbar.
The flask was then placed on a hotplate=stirrer and heated to 60 ꢀC, whereby the
1
smooth evolution of N2 occurred. After 1 h, H NMR showed all the acyl azide
13 was consumed. The solvent was rotary evaporated, and the remaining liquid
was distilled under reduced pressure to give 10.5 g of the title compound as a pale
yellow liquid (91%). dH (CDCl3): 6.77 (d, J ¼ 7.9 Hz, 1H), 6.69 (d, J ¼ 1.7 Hz, 1H),
6.66 (dd, J ¼ 7.5 and 1.9 Hz, 1H), 5.96 (s, 2H), 3.75 (m, 1H), 2.72 (m, 2H), 1.29
(d, J ¼ 6.5 Hz, 3H); dC (CDCl3): 147.94, 146.71, 131.47, 122.88, 122.59, 109.69,
108.48, 101.16, 53.03, 44.79, 22.93. Elemental analysis calculated for C11H11NO3:
C, 64.38; H, 5.40; N, 6.83. Found: C, 64.60; H, 5.46; N, 6.85.
Racemic tert-Butyl N-{3-(3,4-methylenedioxyphenyl)-
2-propyl}carbamate (15)
A 500-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 100 mL anhydrous THF, 5.4 g tBuOH (73 mmol, 2 equiv), and 4 g KOtBu
(36.5 mmol, 1 equiv). The mixture was stirred in an ice bath, and then a solution of
7.49 g 14 (36.5 mmol) dissolved in 25 mL anhydrous THF was added by addition
funnel over 10 min. All the solids dissolved, and the mixture became clear and light
yellow in color. The cooling bath was removed, and the mixture was stirred at rt for
1 h. Water (100 mL) containing 2.09 mL glacial HOAc (36.5 mmol, 1 equiv) was added.
The phases were separated, and the aqueous phase was extracted twice with 50-mL
portions of Et2O. The organic phases were collected and washed with 50 mL H2O
followed by 50 mL brine. After drying over 3 g anhydrous MgSO4, the solvent was
rotary evaporated, leaving 9.27 g of a pale yellow oil that slowly crystallized (91%).
The crude product was recrystallized from hexanes to obtain the title compound as
colorless needles. Mp 51–53ꢀC. dH (CDCl3): 6.72 (d, J ¼ 7.8 Hz, 1H), 6.67 (d,
J ¼ 1.2 Hz, 1H), 6.61 (dd, J ¼ 7.7 and 1.1 Hz, 1H), 5.90 (s, 2H), 4.49 (bs, NH), 3.82 (pent,
J ¼ 6.3 Hz, 1H), 2.74 (dd, J ¼ 13.5 and 5.9 Hz, 1H), 2.57 (dd, J ¼ 13.9 and 7.2 Hz, 1H),
1.43 (s, 9H), 1.08 (d, J ¼ 6.8, 3H); dC (CDCl3): 155.38, 147.65, 146.45, 132.20, 122.44,
109.89, 108.19, 100.87, 79.21, 47.76, 42.84, 28.52, 20.21. Elemental analysis calculated
for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.36; H, 7.53; N, 4.97.
Racemic tert-Butyl N-{3-(3,4-Methylenedioxyphenyl)-2-propyl}-N-
methylcarbamate (16)
A 250-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 6.38 g 15 (23 mmol) and 50 mL anhydrous DMF. The mixture was cooled in an

SYNTHESIS OF 2-ARYLETHYLAMINES BY THE CURTIUS REARRANGEMENT 1471
ice bath, and 2.55 g KOtBu (23 mmol, 1 equiv) was added in one portion. After the
solid had dissolved (10 min), 2.84 mL iodomethane (6.47 g, 46 mmol, 2 equiv) were
added in one portion. The cooling bath was replaced with a 55 ꢀC bath, and the mix-
ture was stirred for 1 h. A second addition of the same amounts of base and iodide
were added, and after stirring for a total of 2 h at 55 ꢀC, 100 mL H2O were added.
The mixture was extracted with three times with 50-mL potions of hexanes, and
the organic phases were combined. After washing with 50 mL H2O followed by
50 mL brine, the organic phases was dried over anhydrous MgSO4. The solvent
was rotary evaporated, leaving 6.48 g of a pale yellow oil. The oil was distilled under
reduced pressure (0.1 torr) to give 6.1 g of the title compound as a colorless oil (91%).
dH (DMSO; 349 K): 6.77–6.55 (m, 3H), 5.91 (s, 2H), 4.59–4.19 (m, 1H), 2.80–2.48 (m,
5H), 1.39 (s, 9H), 1.14 (d, J ¼ 6.4 Hz, 3H); dC (CDCl3; 300 K): 155.73, 147.68, 146.09,
133.09, 122.06, 109.59, 108.27, 100.92, 79.27, 52.89, 51.72, 40.46, 28.56, 27.73, 18.31,
17.72. Elemental analysis calculated for C16H23NO4: C, 65.51; H, 7.90; N, 4.77.
Found: C, 65.30; H, 7.92; N, 4.57.
Racemic N,a-Dimethyl-2-(3,4-methylenedioxyphenyl)ethylamine (3)
A 1.8-g portion of 16 (6.1 mmol) was dissolved in 50 mL THF and heated to
45 ꢀC, and then 3.42 mL conc. HCl (41 mmol, 6.7 equiv.) was added dropwise over
5 min. The mixture was stirred at this temperature for 3 h, after which time TLC
showed the reaction was complete. After cooling to rt, the mixture was diluted with
50 mL H2O and extracted with 50 mL Et2O. The organic layer was discarded, and the
aqueous layer was basified by slow addition of solid K2CO3. The mixture was
extracted twice with 50-mL portions of Et2O. The organic phases were collected
and washed with 25 mL brine. The organic layer was separated and dried over 3 g
anhydrous MgSO4. After filtration, the solvent was rotary evaporated, leaving a
1.11 g of a colorless oil (95%). The crude oil was further purified by distillation under
reduced pressure (0.1 torr). dH (CDCl3): 6.74 (d, J ¼ 8.0 Hz, 1H), 6.69 (d, J ¼ 1.6 Hz,
1H), 6.63 (dd, J ¼ 7.9 and 1.7 Hz, 1H), 5.92 (s, 2H), 2.73 (hextet, J ¼ 6.5 Hz, 1H),
2.66–2.49 (m, 2H), 2.39 (s, 3H), 1.05 (d, J ¼ 6.2 Hz, 3H); dC (CDCl3): 147.76,
146.05, 133.39, 122.27, 109.63, 108.27, 100.92, 56.57, 43.32, 34.17, 19.80. Solids
formed after storage of this compound in a stoppered flask overnight, as the amine
absorbs atmospheric CO2. Elemental analyses (C, H, N) were carried out, but results
did not correspond to the free amine on this account.
Racemic N,a-Dimethyl-2-(3,4-methylenedioxyphenyl)ethylamine (3)
Oxalate Salt
A 250-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 5.7 g oxalic acid dihydrate (46 mmol, 1.1 equiv) and 100 mL EtOH. After all the
solids had dissolved, a solution of 8.07 g 3 (42 mmol) in 25 mL EtOH was added in
one portion. After 30 min, a white crystalline solid had precipitated, was collected on
a medium glass frit, and air-dried several hours (9.74 g, 76%). No further purification
was necessary. Mp 105–107 ꢀC. dH (DMSO): 8.83 (bs, 3H), 6.89–6.85 (m, 2H), 6.71
(dd, J ¼ 8.0 and 1.5 Hz, 1H), 6.00 (s, 2H), 3.31 (m, 1H), 3.06 (dd, J ¼ 13.2 and 4.3 Hz,

1472
M. SCHULZE
1H), 2.58 (s overlapping m, 4H), 1.09 (d, J ¼ 6.5 Hz, 3H); dC (DMSO): 164.93,
147.39, 146.02, 130.45, 122.38, 109.48, 108.27, 100.86, 55.27, 37.95, 29.67, 14.88.
Elemental analysis calculated for C11H15NO2 ꢂ C2H2O4: C, 55.12; H, 6.05; N, 4.94.
Found: C, 55.09; H, 6.01; N, 4.93.
2-(3,4,5-Trimethoxyphenyl)ethyl Isocyanate (18)
A 250-mL, round-bottomed flask equipped with magnetic stirbar and 100 mL
addition funnel was charged with 50 mL DCE and 5.21 g ethyl chloroformate (1
equiv) and cooled in an ice bath. In a separate flask, a solution of 11.5 g 17
(0.01 mol), 4.84 g TEA (1 equiv), and 50 mL DCE was made. The addition funnel
was charged with the latter solution, which was run in over 20 min. After stirring
1
another 20 min, H NMR showed the reaction was complete. A solution of 4.68
NaN3 (1.5 equiv) in 50 mL H2O was added to the addition funnel, which was run
1
in over 20 min. After stirring another 15 min, TLC and H NMR showed the reac-
tion was complete. In the following steps, the organic phase was kept at <10 ꢀC with
an ice bath. The organic phase was separated and washed in sequence with 50 mL
cold H2O, 50 mL cold saturated aqueous NaHCO3, and finally 50 mL cold brine.
The organic phase was dried over 3 g anhydrous MgSO4 and filtered into a
500-mL, round-bottomed flask containing a magnetic stirbar. A reflux condenser
was attached, and the mixture was heated at 80 ꢀC overnight. The next morning,
1H NMR showed the reaction was complete, and rotary evaporation of the mixture
gave 9.76 of a slightly yellow oil (86%). Reduced pressure distillation (0.1 torr) gave
the title compound as a colorless oil. The product crystallized to a white solid at
ꢃ20 ꢀC and did not melt when returned to room temperature. Mp 26–28 ꢀC. dH
(CDCl3): 6.44 (s, 2H), 3.86 (s, 6H), 3.84 (s, 3H), 3.51 (t, J ¼ 6.6 Hz, 2H), 2.84 (t,
J ¼ 6.6 Hz, 2H); dC (CDCl3): 153.43, 137.21, 133.53, 122.68, 105.98, 60.81, 56.15,
44.29, 38.08. Elemental analysis calculated for C12H15NO4: C, 60.75; H, 6.37; N,
5.9. Found: C, 60.64; H, 6.23; N, 6.06.
2-(3,4,5-Trimethoxyphenyl)ethylamine (4) Hydrogen Sulfate
A 100-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 3.89 g 18 (16.4 mmol) and a solution of 2.73 mL conc. H2SO4 (49.2 mmol, 3
equiv) in 15 mL H2O. The mixture was heated to 80 ꢀC for 1 h, whereupon evolution
of CO2 was observed, and the mixture became a homogeneous solution. After cool-
ing to 10 ꢀC, a portion of the product precipitated as a white crystalline solid and was
filtered on a medium-porosity glass frit (1.1 g). The reaction mixture was rotary eva-
porated to give a second crop of product, which was washed with EtOH and filtered
on a medium-porosity glass frit (2.46 g, total yield 70%). Recrystallization from
EtOH gave the title compound as colorless needles. Mp 140–155 ꢀC. dH (DMSO):
7.82 (bs, OH), 6.6 (s, 2H), 6.57 (bs, NH3), 3.78 (s, 6H), 3.63 (s, 3H), 3.06 (m, 2H),
2.83 (m, 2H); dH (D2O): 6.71 (s, 2H), 3.88 (s, 6H), 3.79 (s, 3H), 3.29 (t, J ¼ 7.3 Hz,
2H), 2.97 (t, J ¼ 7.3 Hz); dC (DMSO): 153.01, 136.38, 133.03, 106.21, 60.01, 55.95,
40.25, 33.29. Elemental analysis calculated for C11H17NO3 ꢂ H2SO4: C, 42.71; H,
6.19; N, 4.53. Found: C, 42.78; H, 6.14; N, 4.56.

SYNTHESIS OF 2-ARYLETHYLAMINES BY THE CURTIUS REARRANGEMENT 1473
2-(3,4,5-Trimethoxyphenyl)ethylamine (4) Hemisulfate Hydrate
A 100-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 2.24 g 18 (9.5 mmol) and a solution of 460 mg conc. H2SO4 (4.75 mmol, 0.5
equiv) in 10 mL H2O. The mixture was heated to 80 ꢀC for 1 h, whereupon evolution
of CO2 was observed, and the mixture became a homogeneous solution. After cool-
ing to rt, the product precipitated as colorless needles and was filtered on a
medium-porosity glass frit (2.39 g, 87%). The solid was recrystallized from isopro-
panol to give the title compound as colorless needles. Mp 162–180 ꢀC (lit.[72]
172–183 ꢀC). dH (DMSO): 6.55 (s, 2H), 3.67 (s, 6H), 2.76 (s, 3H), 3.03 (m, 2H),
2.93 (m, 2H); dH (D2O): 6.71 (s, 2H), 3.89 (s, 6H), 3.79 (s, 3H), 3.29 (t, J ¼ 7.3 Hz,
2H), 2.98 (t, J ¼ 7.4 Hz, 2H); dC (DMSO): 152.78, 136.09, 134.02, 105.90, 59.78,
55.64, 40.52, 33.74. Elemental analysis calculated for C11H17NO3 ꢂ 0.5 H2SO4 ꢂ 1.5
H2O: C, 48.21; H, 7.12; N, 5.11. Found: C, 48.00; H, 7.36; N, 5.08.
ACKNOWLEDGMENT
The financial support of the National Institute on Drug Abuse is gratefully
acknowledged.
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