1238
D. DE BOER ET AL .
base peak. Prior to GC/MS and if speciÐed, the synthe-
sized compounds were converted into triÑuoroacetyl
(TEA) derivatives. Ethyl acetate (50 ll) and 50 ll of
TFAA were added to dry residues and the mixture was
heated for 20 min at 60 ¡C. Excess of organic solvent
and TFAA were removed by evaporation and the
residue was dissolved in 100 ll of ethyl acetate. A 1 ll
aliquot was injected into the GC/MS instrument.
Melting points were determined in capillary tubes and
are uncorrected.
was extracted with two consecutive portions of 50 ml of
dichoromethane, brought to pH 10 with solid sodium
hydroxide, saturated with sodium chloride and
extracted three times with 50 ml portions of dichorome-
thane. The combined extracts were dried (magnesium
sulfate) and the solvent was removed in vacuo. The
resulting oil was dissolved in propan-2-ol and acidiÐed
with concentrated hydrochloric acid. A white solid sub-
stance crystallized spontaneously, was Ðltered o† and
washed Ðrst with propan-2-olÈdiethyl ether (1 : 1) and
then with diethyl ether. The product was isolated as
(RS)-MDA hydrochloride (m.p. 187È188 ¡C, lit.21 187È
Starting materials (IÈIII) for the synthesis of the refer-
ence standards were produced in several batches.
188 ¡C; yield 31%). 1H NMR (300.07 Hz; CDCl ÈTFA-
3
d (6 : 1; v/v)): d 1.45 (d, 3 H, J \ 6.6 Hz, CCH ), 2.86
3
Piperonyl methyl ketone (I). Safrole was isomerized to
isosafrole15 by heating with 2.5 molar equivalents of
potassium hydroxide for 6.5 h at 120 ¡C. After cooling
to room temperature, the clear golden yellow solution
was decanted (average yield [90%). The crude product
was used in the next step as soon as possible, because
isosafrole polymerizes slowly in the presence of mois-
ture. Piperonyl methyl ketone was obtained by hydro-
gen peroxide oxidation of crude isosafrole followed by
an acid-catalyzed rearrangement.16 Distillation under
(dd, 1 H, J \ 14.5 Hz, J \ 8.2 Hz, H-1), 2.95 (dd, 1
AB
BX
H, J \ 14.5 Hz, J \ 6.3 Hz, H-1), 3.68 (m, 1 H,
AB
AX
CHN), 5.96 (s, 2 H, OCH O), 6.67 (dd, 1 H, J \ 7.8 Hz,
2
o
J \ 1.8 Hz, H-6@), 6.69 (d, 1 H, J \ 1.8 Hz, H-2@), 6.79
m
m
(d, 1 H, J \ 7.8 Hz, H-5@), 6.9 (bs, 3 H, NH `). 13C
o
3
NMR (75.5 Hz; CDCl ÈTFA-d (6 : 1; v/v)): d 18.0
3
(CH ), 40.3 (CH ), 51.2 (CH), 101.2 (CH O), 109.0 (C-2@),
3
2
2
109.2 (C-5@), 122.5 (C-6@), 127.8 (C-1@), 147.3 (C-4@), 148.3
(C-3@). GC/MS (TFA derivative): m/z, M`~ 275(15),
162(38), 135(100), 77(16), 69(11).
reduced pressure yielded
a clear yellow product
(average yield 40%). 1H NMR (90 Hz; CCl ): d 1.99 (s,
4
3 H, CH ), 3.47 (s, 2 H, CH CO), 5.88 (s, 2 H OCH O),
(RS)-HMMA. (RS)-HMMA (1-(3-methoxy-4-hydroxy-
phenyl)-2-methylaminopropane) was prepared from III
by reductive amination with sodium cyano-
borohydride.21,22 To a solution of 3.0 g of methylamine
hydrochloride in 20 ml of methanol were added 2.3 g of
III followed by 1.0 g of sodium cyanoborohydride. The
solution was treated as in the reductive amination of
(RS)-MDA, except that the extraction was done with
ethyl acetate instead of dichloromethane. Light brown
crystals were obtained, which were Ðltered o† and
washed Ðrst with propan-2-olÈdiethyl ether (1 : 1) and
then with diethyl ether. The product was isolated as
(RS)-HMMA hydrochloride (m.p. 181È189 ¡C; yield
3
2
2
6.49È6.72 (m, 3 H, aromatic). GC/MS: m/z, M`~
178(26), 135(100), 77(23).
b-Nitroisoeugenol (II). Condensation of vanillin with
nitroethane was carried out by the Knoevenagel con-
densation.17,18 b-Nitroisoeugenol was obtained as
yellow crystals, Ðltered o† and air dried (average
yield[55%). 1H NMR (90 Hz; CDCl ): d 2.48 (s, 3 H,
3
CCH ), 3.95 (s, 3 H, OCH ), 5.91 (bs, 1 H, OH), 6.85È
3
3
7.17 (m, 3 H, aromatic), 8.08 (s, 1 H, CH). GC/MS (TFA
derivative): m/z, M`~ 305(100), 258(52), 192(22), 178(16),
162(32), 161(49), 151(19), 147(35), 139(12), 131(36),
119(14), 115(66), 105(17), 103(34), 102(13), 91(27), 89(18),
79(18), 77(32), 69(68), 65(22), 63(15).
12%). 1H NMR (300.07 Hz; CDCl ÈTFA-d (6 : 1; v/v)):
3
d 1.41 (d, 3 H, J \ 6.6 Hz, CCH ), 2.80 (m, 3 H, NCH ),
3
3
2.88 (dd, 1 H, J \ 14.2 Hz, J \ 7.2 Hz, H-1), 3.00
AB
(dd, 1 H, J \ 14.2 Hz, J \ 7.2 Hz, H-1), 3.53 (m, 1
AB AX
H, CH), 3.88 (s, 3 H, OCH ), 6.70 (dd, 1 H, J \ 8.1 Hz,
BX
Vanillyl methyl ketone (III). b-Nitroisoeugenol was
reduced with iron(III) chloride, iron powder and con-
centrated hydrochloric acid.19 The resulting dark
brown oil was puriÐed by “dry ÑashÏ column chromatog-
raphy.20 The product was eluted from a silica gel
column with tolueneÈdiethyl ether (1 : 2) (yield 68%). 1H
NMR (90 Hz; CDCl ): d 2.12 (s, 3 H, COCH ), 3.64 (s,
3
o
J \ 1.8 Hz, H-6@), 6.73 (d, 1 H, J \ 1.8 Hz, H-2@), 6.90
m
m
(d, 1 H, J \ 8.1 Hz, H-5@), 7.10 (bs, 2 H, NH `), 11.38
o
2
(s, 1 H, OH). 13C NMR (75.5 Hz; CDCl ÈTFA-d (6 : 1;
3
v/v)): d 15.3 (CH ), 30.8 (NCH ), 39.4 (CH ), 55.9
3
3
2
(OCH ), 58.2 (CH), 112.0 (C-5@), 115.2 (C-2@), 122.0 (C-6@)
3
3
3
2 H, CH ), 3.90 (s, 3 H, OCH ), 5.95 (bs, 1 H, OH),
, 126.9 (C-1@), 144.1 (C-4@), 147.1 (C-3@). GC/MS (TFA
2
3
6.66È7.02 (m, 3 H, aromatic). GC/MS (TFA derivative):
m/z, M`~ 276(100), 233(75), 205(16), 137(16), 107(15),
106(10), 105(16), 77(16), 69(32), 65(13).
derivative): m/z, M`~ 387(\1), 260(24), 154(100),
110(24), 69(14).
(RS)-HMA. (RS)-HMA (1-(3-methoxy-4-hydroxyphenyl)
-2-aminopropane) was prepared from II by reduction
with lithium aluminium hydride essentially according to
Ramirez and Burger.17 Instead of the Soxhlet extraction
technique, 7.0 g of II were dissolved in 50 ml of dry
tetrahydrofuran and the solution obtained was added
dropwise to a well stirred mixture of 2.5 g of lithium
aluminium hydride and 200 ml of dry diethyl ether. The
dark red picrate obtained was dissolved in propan-2-ol
and acidiÐed with concentrated hydrochloric acid. A
brown solid crystallized spontaneously and was Ðltered
o† and washed Ðrst with propan-2-olÈdiethyl ether
(RS)-MDA. (RS)-MDA (1-(3,4-methylenedioxyphenyl)-2-
aminopropane) was prepared from I by reductive amin-
ation with sodium cyanoborohydride.21,22 To a solu-
tion of 17.7 g of anhydrous ammonium acetate in 60 ml
of methanol were added 4.2 g of I followed by 1.7 g of
sodium cyanoborohydride. The solution was stirred at
ambient temperature for 72 h and kept at pH 6È7 by
gradual addition of concentrated hydrochloric acid.
After adding 100 ml of demineralized water, the pH was
brought to 2 with concentrated hydrochloric acid.
Methanol was removed in-vacuo. The aqueous solution
( 1997 John Wiley & Sons, Ltd.
JOURNAL OF MASS SPECTROMETRY, VOL. 32, 1236È1246 (1997)
De Boer
