A novel synthesis of isoeugenol, [ring-(U)-14C]

Article abstract of DOI:10.1002/jlcr.3329

A novel method for the preparation of isoeugenol, [ring-(U)-¹⁴C] is presented. Phenols and phenyl esters substituted in the para position with 1-hydroxyethyl or 1-hydroxypropyl acetate esters when treated with 1,8-diazabicyclo[5.4.0]undec-7-ene in dimethylformamide (DMF) eliminate the alkyl carboxylate function to give the unsaturated compound. The reaction fails with unsubstituted or ether substituted phenyl 1-hydroxyacetate esters.

Full text of DOI:10.1002/jlcr.3329

Research article
Received 7 June 2015,
Revised 4 July 2015,
Accepted 28 July 2015
Published online 26 August 2015 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3329
14
A novel synthesis of isoeugenol, [ring-(U)- C]
*
John E. Immoos Jr.
A novel method for the preparation of isoeugenol, [ring-(U)-14C] is presented. Phenols and phenyl esters substituted in the
para position with 1-hydroxyethyl or 1-hydroxypropyl acetate esters when treated with 1,8-diazabicyclo[5.4.0]undec-7-ene
in dimethylformamide (DMF) eliminate the alkyl carboxylate function to give the unsaturated compound. The reaction fails
with unsubstituted or ether substituted phenyl 1-hydroxyacetate esters.
Keywords: isoeugenol; guaiacol; deacetylation; carbon-14; quinone methide
Reduction of the resulting ketone with lithium aluminum hydride in
Introduction
diethyl ether produced the diol, 7. Reduction of the ketone with
Isoeugenol is found in ylang-ylang, nutmeg, and other essential
sodium borohydride at room temperature in isopropanol proceeded
oils. It has also been used extensively as a model compound in
very slowly, taking 4 to 5 days to reach completion. Reduction with
the study of lignin degradation.1–4 Isoeugenol from natural and
NaBH4 in refluxing dimethoxyethane was also very slow and
synthetic sources contains varying amounts of cis and trans
decomposition was observed. The diol, 7, which appeared to be
isomers with the trans isomer in most cases, being the major
component. Methods for its synthesis include the thermal or
unstable in the presence of acid, was converted to the diacetate
using acetyl chloride and triethylamine in diethyl ether. Esterification
chemical isomerization of eugenol,5–7 reaction of vanillin with a
in dichloromethane led to partial decomposition because the
Wittig reagent,8,9 and the reaction of phenylmagnesium
triethylammonium hydrochloride side product is significantly soluble
bromide with isosafrole.10 The reaction of vanillin with a Wittig
in dichloromethane and is acidic enough to cause degradation.
reagent appeared to be the most attractive with regard to yield;
Attempts were made to convert the diol directly to isoeugenol,
[ring-(U)-14C] by dehydration with phosphorous pentoxide or with
however, attempted formylation of guaiacol with various
formylating reagents failed to produce vanillin. An alternative
sulfuric acid. This led only to significant decomposition of the diol.
Isoeugenol, [ring-(U)-14C], 10 was produced from the diester, 8 in
route was developed, which produced isoeugenol, [ring-
(U)-14C] from phenol, [(U)-14C] in an overall yield of 20.8%.
two steps. In the first step, the acetate group on the propyl side chain
Guaiacol, [ring-(U)-14C], an intermediate, was esterified with
was removed using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
dimethylformamide at 80o to give 1-(4-acetoxy-3-methoxy[phenyl-
propionyl chloride, and the resulting ester was rearranged to
4′-hydroxy-3′-methoxypropiophenone, [ring-(U)-14C] (Fries reaction).
11 Reduction of the ketone to an alcohol followed by esterification
of the phenol and propyl hydroxyl groups with acetyl chloride
gave the diacetate. Isoeugenol was then generated by elimination
of the acetate group on the propyl substituent to produce
isoeugenyl acetate followed by regeneration of the phenolic
function by reaction with sodium methoxide in methanol. It was
discovered that other carboxylate esters could be used but an
ester function or a free hydroxy group in the position para to the
alkyl acetate substituent was necessary for the reaction to proceed.
Phenyl compounds with ether groups in the para position or
unsubstituted phenyl compounds did not eliminate the alkyl
acetate group even at elevated temperatures.
(U)-14C])-prop-1-ene, 9. The reaction could also be completed in
refluxing benzene but considerably longer times (18 to 24 h versus
2 to 3 h for DMF) were required. The reaction was also attempted with
triethylamine in DMF. However, after 48 h at 80 °C, the reaction was
only 14% complete. The presence of the acetate group (or other
carboxylate groups or hydroxyl group) in the position para to the
benzylic acetate group appeared to be essential for this reaction to
occur. For example, none of the corresponding alkene was formed if
the reaction was carried out with unsubstituted phenyl-1-alkanol
acetates or with phenyl-1-alkanol acetates substituted with ether
groups in the para position even at temperatures as high as 160 °C.
However, reaction of 1-(4-acetoxyphenyl)-prop-1-yl acetate or 1-(4-
acetoxyphenyl)-eth-1-yl acetate with DBU in DMF at 80 °C gave the
corresponding alkene in approximately 80–88% yield. Reaction of
the diester with DBU gave a mixture of isoeugenyl acetate, 9 and
isoeugenol, 10. It was determined that the isoeugenol was formed
Results and discussion
Guaiacol, [ring-(U)-14C], 4, was produced from phenol, [ring-
(U)-14C] using a procedure similar to ones used previously.12,13
This procedure produced guaiacol, [ring-(U)-14C] in a 77.6%
radiochemical yield (Scheme 1). The guaiacol, [ring-(U)-14C] thus
produced was then esterified with propionyl chloride to give
2-methoxyphenylpropionate, [ring-(U)-14C], 5 (Scheme 2.). This
ester was rearranged to 4′-hydroxy-3′-methoxypropiophenone,
[ring-(U)-14C], 6, using the Fries reaction at 60 °C in nitrobenzene.14,15
Moravek Biochemicals, Inc., 577 Mercury Lane, Brea, CA 92821, USA
*Correspondence to: John Immoos, Moravek Biochemicals, Inc., 577 Mercury
Lane, Brea, CA 92821, USA.
E-mail: jimmoos@moravek.com
J. Label Compd. Radiopharm 2015, 58 419–424
Copyright © 2015 John Wiley & Sons, Ltd.

J. E. Immoos Jr.
Scheme 1. Synthesis scheme for guaiacol, [ring-U-14C].
Scheme 2. Synthesis scheme for Isoeugenol, [ring-U-14C].
by partial hydrolysis of the phenyl ester during aqueous workup. with tert-butyldimethylsilyl (TBDMS) chloride and DBU in benzene
Analysis by gas chromatography–mass spectrometry showed that (compound 8d).17 The monoester or mono-TBDMS derivative was
very little isoeugenol was present before the aqueous quench. In formed preferentially because steric hindrance or reaction kinetics
the second step, the mixture, which was used without purification, greatly limited disubstitution. After isolation and purification, the
was stirred at room temperature with a solution of sodium methoxide acetate ester of the propyl group was formed using acetyl
in methanol to remove the acetyl group remaining on the phenol. The chloride/triethylamine in each case (Scheme 3). To produce
isoeugenol produced from several runs in this manner contained 93% compound 8d, the TBDMS protecting group was removed with
to 97% of the trans isomer.
triethylamine trihydrofluoride in THF using a modification of a
In order to attempt to determine the mechanism of the reaction, literature procedure.18 The pivaloyl ester compound, 8f, was
other phenolic esters and ether or unsubstituted phenyl subjected to the reaction with DBU in DMF at 80 °C. After 31 h,
compounds were prepared. The results of this study are shown in the reaction mixture consisted of 33.5% diester starting material,
Table 1. Compound 8a was prepared from commercially available 41.3% isoeugenyl pivaloate, and 25.2% isoeugenol. The reaction
1-phenyl-1-propanol using acetyl chloride and triethylamine in of the benzoate/acetate compound, 8e, under the same conditions
dichloromethane. Compounds 8b and 8c were synthesized by proceeded to completion in 12 h. In this instance, considerably
reducing the commercially available propiophenones with sodium more (36%) isoeugenol was formed along with 9% isoeugenyl
borohydride in 2-propanol followed by esterification with acetyl acetate. Formation of the latter would imply that the acetate ion
chloride. Compounds 8d, 8e, and 8f were prepared from liberated from the alkyl group could be interacting with the base-
compound 11 that, in turn, was obtained from the reaction acyl complex forming acetic benzoic anhydride, which could
of ethyl Grignard with vanillin in THF.16 The phenol group was first produce isoeugenyl acetate. Given the results from this limited
esterified with benzoyl chloride or pivaloyl chloride and study, a reaction mechanism is proposed that involves a quinone
triethylamine in diethyl ether (compounds 8e and 8f) or reacted methide intermediate (Scheme 4).19
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J. Label Compd. Radiopharm 2015, 58 419–424

J. E. Immoos Jr.
polyester. Gas chromatography was carried out with a Shimadzu GC-
14A on a 183 × 0.32 cm stainless steel column packed with 10% OV-101
on Chromosorb-W. HPLC analysis was performed using a Phenomenex
Prodigy 5 ODS(2) 4.6 × 250 mm, 5 μ column. Purification of intermediates
was carried out using a 4 × 48 cm column with silica gel (200–400 mesh,
60 Å). 1H NMR spectra were obtained at ambient temperature at 400 MHz
using a Bruker 400 ultrashield plus spectrometer.
Table 1. Reaction of various 1-phenyl-1-alkyl acetates with
DBU in DMF
2-[Phenoxy-(U)-14C]-5-nitrobenzophenone (1)
Phenol-U-14
C (0.538 g, 5.67 mmoles, 170 mCi, 30 mCi/mmole) was
dissolved in dimethylformamide (6.5 ml) in a 100 ml flask equipped with
a magnetic stir bar and reflux condenser. Potassium hydroxide, 85%
(0.449 g, 6.80 mmoles) was crushed to a powder and added to the flask.
After stirring for 5 min, 2-chloro-5-nitrobenzophenone (1.513 g,
5.67 mmoles) was added. The mixture was then heated at 150 °C in an
oil bath under a nitrogen atmosphere for 45 min. After cooling to room
temperature, 1 N NaOH (10.3 ml) and water (30 ml) were added with
stirring. The solid product precipitated and was extracted using ethyl
acetate. Numerous extractions were needed to remove all radioactivity
from the reaction mixture. The resulting ethyl acetate solution was
washed with water (15 ml × 2) and then dried with anhydrous
magnesium sulfate. The solution was filtered from the drying agent
and the solvent removed under vacuum with a rotary evaporator. The
orange-brown solid was placed under high vacuum until constant
weight was achieved. The product was purified by flash chromatography
using 10:1 benzene : ethyl acetate to produce 1.638 g, (5.13 mmoles,
90.5% yield) of 2-[phenoxy-(U)-14C]-5-nitrobenzophenone. A small
portion was recrystallized from benzene to give an analytically pure
Ester
R
R1
R2
R3
Yield of 9, %
8
OAc
H
–O–CH2–O–
OCH3
OH
OCH3
H
OAc
OAc
OAc
OAc
OAc
OAc
OAc
CH3
CH3
CH3
CH3
CH3
CH3
CH3
85–90a
0
0
8a
8b
8c
8d
8e
8f
H
0
OCH3
OCH3
OCH3
94b
54c
66d
OBz
Opiv.
aReaction complete in 2 h, product was a mixture of
alkenylphenylacetate (85–90%) and alkenylphenol.
bReaction complete in 2 h, isoeugenol is the sole product.
cReaction complete in 12 h. Product also contained 36%
isoeugenol and 9% isoeugenyl acetate.
sample. 1H NMR (400 MHz, CD3COCD3),
δ 8.41–8.39 (m, 2H,
dReaction incomplete after 31 h.
nitrophenyl-ortho), 7.94 (d, J = 7.2 Hz, 2H, benzoyl-ortho), 7.68 (t,
J = 7.4 Hz, 1H, benzoyl-para), 7.56 (t, J = 7.6 Hz, 2H, benzoyl-meta),
7.44 (t, J = 7.4 Hz, 2H, phenoxy-meta), 7.26 (t, J = 7.2 Hz, 1H, phenoxy-
para), 7.13–7.06 (m, 2H, phenoxy-ortho, 1H nitrophenyl-meta).
2-[2′-Hydroxyphenoxy-(U)-14C]-5-nitrobenzophenone (2)
To 2-[2′-Phenoxy-(U)-14C]-5-nitrobenzophenone (1.638 g, 5.13 mmoles,
153.9 mCi) contained in a 50 ml flask was added 3.1 ml concentrated
sulfuric acid. The mixture turned red, and the flask was swirled to dissolve
the entire solid. The mixture was then stirred for an additional half hour
at room temperature. Glacial acetic acid (18 ml) was added with stirring
followed by 30% hydrogen peroxide (4.1 ml) in one portion. An
exothermic reaction occurred followed by the disappearance of the red
color and formation of a tan solid. The mixture was stirred an additional
3 h at room temperature and then added to crushed ice in a 250 ml
beaker. The reaction flask was rinsed with 10 ml of water and added to
the beaker. The product was filtered and washed with water and then
dissolved off the filter into a 100 ml flask using ethyl acetate. Water was
removed from the ethyl acetate solution; then the solution was dried
over magnesium sulfate. The solution was filtered, and the solvent
removed to give 1.784 g of an orange solid. Purification by flash
chromatography using 8:1 benzene : ethyl acetate produced 1.715 g,
(5.10 mmole, 153 mCi, 99.4% yield) of light orange product. A small
portion was recrystallized using ethyl acetate to give an analytically pure
sample. 1H NMR (CD3COCD3), δ 8.96 (s, 1H, OH), 8.38–8.36 (m, 2H,
nitrophenyl-ortho), 8.00 (d, J = 7.6 Hz, 2H, benzoyl-ortho), 7.67 (t,
J = 7.6 Hz, 1H, benzoyl-para), 7.56 (t, J = 7.6 Hz, 2H, benzoy-lmeta), 7.15
(t, J = 7.6 Hz, 1H, phenoxy-para), 7.08 (d, J = 8.0 Hz, 1H, nitrophenyl-meta),
7.04 (d, J = 8.0 Hz, 1H, phenoxy-ortho), 6.95 (d, J = 8.8 Hz, 1H, phenoxyl-
meta), 6.90 (t, J = 7.2 Hz, 1H, phenoxy-meta).
Scheme 3. Reaction sequence to prepare compounds 8d–8f from Table 1.
Scheme 4. Proposed mechanism for the reaction of p-acetoxyalkylphenyl esters
with a base.
2-(2′-Methoxy[phenoxy-(U)-14C])-5-nitrobenzophenone (3)
Experimental
An ether solution of diazomethane generated from 10.75 g of N-methyl-N-
nitroso-p-toluenesulfonamide (Diazald) and contained in
a 250 ml
Materials and methods
Erlenmeyer flask was cooled in an ice bath. 2-[2′Hydroxyphenoxy-
(U)-14C]-5-nitrobenzophenone (1.715 g, 5.10 mmoles, 153 mCi) was
dissolved in a mixture of diethyl ether (27 ml) and methanol (5.3 ml) and
slowly added with stirring to the diazomethane solution. The flask was
All commercially available reagents were used as purchased. Thin-layer
chromatography was carried out using silica gel with fluorescent
indicator, (250 μM thickness, 5–17 μM particle size, 60 Å pore size) on
J. Label Compd. Radiopharm 2015, 58 419–424
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J. E. Immoos Jr.
covered with parafilm and placed in a refrigerator at 4 °C for 16 h. The
solution was then cooled in an ice bath and 2.5 ml glacial acetic acid added
dropwise to destroy the excess diazomethane. A small amount of solid
material was filtered, and the solvents were removed using a rotary
cooled in an ice bath, and 2-methoxy[phenyl-(U)-14C]propionate (0.766 g,
4.20 mmoles) was added dropwise by syringe through the septum over
10 min. The flask that contained the ester was rinsed with 1 ml nitrobenzene
and added to the reaction mixture. The mixture was stirred in the ice bath for
evaporator. The product was placed under high vacuum to a constant an additional 5 min and then heated at 60 °C for 3 h. A solid formed during
weight. Purification by flash chromatography using 10:1 benzene : ethyl this time. The mixture was cooled to room temperature and added to 1 N
acetate produced 1.682 g, (4.83 mmole, 144.9 mCi, 94.7% yield) of yellow- hydrochloric acid (50 ml) cooled in an ice bath. The reaction flask was rinsed
orange solid. 1H NMR (CD3COCD3). δ 8.37 (s, 1H, nitrophenyl-ortho), 8.33
(d, J = 9.2 Hz, 1H, nitrophenyl-ortho), 7.98 (d, J = 7.6 Hz, 2H, benzoyl-ortho),
7.68 (t, J = 7.2 Hz, 1H, benzoyl-para), 7.58 (t, J = 7.2 Hz, 2H, benzoyl-meta),
7.29 (t, J = 8.0 Hz, 1H, phenoxy-para), 7.18 (d, J = 8.0 Hz, 1H, nitrophenyl-
meta), 7.11 (d, J = 8.0 Hz, 1H, phenoxy-meta), 7.00 (t, J = 7,6 Hz, 1H,
with cold 1 N hydrochloric acid (3 ml) and ether (5 ml) and added to the bulk
product. The ether layer was removed and the aqueous layer extracted with
ether (8 ml × 3). The product was then extracted from the ether solution with
2 N sodium hydroxide (10 ml × 3). The resulting basic solution was washed
with ether (10 ml × 3) and then cooled in an ice bath and acidified with
phenoxy-meta), 6.84 (d, J = 9.2 Hz, 1H, phenoxy-ortho), 3.79 (s, 3H, concentrated hydrochloric acid to pH 2. The product was extracted with ether
methoxy).
and dried over magnesium sulfate. After removal of the solvent the
product was purified by flash chromatography with 3:1 hexane : ethyl
acetate to produce 0.527 g, (2.91 mmoles, 87.3 mCi, 69% yield) of 4′-
hydroxy-3′-methoxypropiophenone, [ring-(U)-14C] as an off-white solid.
1H NMR (CDCl3), δ 7.56–7.53 (m, 2H, benzoyl-ortho), 6.95 (d, 1H, J = 8.7 Hz,
benzoyl-meta), 6.10 (s, 1H, OH), 3.95 (s, 3H, methoxy), 2.96 (q, J = 7.2 Hz,
2H, CH2), 1.22 (t, J = 7.2 Hz, 3H CH3).
Guaiacol, [ring-(U)-14C] (4)
Piperidine (4.8 ml, 48.5 mmoles) was added to 2-(2′-methoxy[phenoxy-
(U)-14C])-5-nitrobenzophenone (1.682 g, 4.83 mmoles, 144.9 mCi) in a
100 ml flask equipped with a reflux condenser. The mixture was heated
to 150 °C in an oil bath for 1.5 h and then cooled to room temperature
and diluted with 15 ml of benzene. The mixture was cooled in an ice bath
and 2 N H2SO4 (15 ml) was added. The mixture was stirred, the aqueous
layer removed, and the organic layer was washed again with 2 N H2SO4
1-(4-Hydroxy-3-methoxy[phenyl-(U)-14C])-propan-1-ol (7)
To a 50 ml flask containing 4′-hydroxy-3′-methoxypropiophenone, [ring-
(15 ml × 2). The aqueous acid washes were saturated with sodium sulfate (U)-14C] (0.527 g, 2.91 mmoles) was added 6 ml of anhydrous diethyl
and extracted with diethyl ether to remove all radioactivity. The ether ether. A septum vented with a needle connected to a dry nitrogen
extracts were combined with the benzene solution, and the resulting bubbler was placed on the flask, and the mixture was cooled in an ice
solution was washed with 2 N NaOH (8 ml × 3). The combined basic
bath. A solution of lithium aluminum hydride (3 ml, 1.0 M in diethyl ether,
solution was washed with 10 ml diethyl ether. The basic aqueous mixture 3 mmoles) was added by syringe dropwise over 5 min. The mixture was
was cooled in an ice bath and acidified to pH 2 with concentrated
stirred in the ice bath for 5 min and then at room temperature for 16 h.
hydrochloric acid. The product was extracted from the aqueous mixture
The flask was cooled in an ice bath, and water (1 ml) was added dropwise
with diethyl ether (10 ml × 3). The ether solution was dried over followed by 15% NaOH (1 ml) and water (3 ml). The mixture was then
magnesium sulfate, filtered, and the solvent removed under vacuum. filtered through Celite and the filter cake washed with water (10 ml).
The crude product was purified on silica gel using 4:1 pentane : diethyl
ether to give 2.130 g of a mixture of product and residual solvents.
Analysis of the product by gas chromatography (temp. program: 120 °C
for 2 min, ramp to 260 °C at 20o/min) showed it to contain 25.8%
guaiacol-ring-U-14C. Calibration with known concentrations of guaiacol
in diethyl ether showed the mixture to contain 0.550 g, (4.40 mmoles,
132.0 mCi, 91.1% yield) of guaiacol, [ring-(U)-14C]. 1H NMR (CDCl3) δ
6.95–6.81(m, 4H, aromatic), 5.74 (s, 1H, OH), 3.83 (s, 3H, CH3).
The pH was adjusted to approximately 3 with 3 N hydrochloric acid.
The aqueous solution was saturated with sodium chloride and extracted
with ether until all radioactivity was removed. The ether solution was
washed with saturated sodium bicarbonate (10 ml). The ether layer was
removed and the aqueous layer was extracted again with ether (10 ml).
The combined ether solution was dried with magnesium sulfate. The
product was purified by flash chromatography using 2:1 hexane : ethyl
acetate to produce 0.451 g (2.47 mmoles, 74.2 mCi, 85% yield) of a white
solid. 1H NMR (CD3COCD3), δ 7.39 (s, 1H, C6H3-OH), 6.97 (d, J = 1.5 Hz, 1H,
phenol-ortho), 4.49–4.43 (m, 1H, CH-OH), 3.98 (d, J = 4.2 Hz, 1H, CH-OH),
3.83 (s, 3H, methoxy), 1.75–1.59 (m, 2H, CH2), 0.87 (t, J = 7.5 Hz, 3H, CH3).
2-Methoxy[phenyl-(U)-14C]propionate (5)
Diethyl ether (15 ml) and triethylamine (0.854 g, 8.44 mmoles) were
added to guaiacol, [ring-(U)-14C] (4.22 mmoles, 0.524 g, 132.0 mCi) in a
50 ml flask. A septum was placed on the flask, and the flask placed under
a dry nitrogen atmosphere. The mixture was cooled in an ice bath, and
propionyl chloride (0.781 g, 8.44 mmoles) was added dropwise by
syringe. The mixture was stirred for 5 min in the ice bath and then for
3 h at room temperature. The mixture was then cooled in an ice bath
and washed with water (10 ml × 3). The ether solution was dried with
magnesium sulfate, filtered, and the solvent removed under vacuum to
leave an orange oil. The product was purified by flash chromatography
using 5:1 petroleum ether (boiling point 35–60 °C) : diethyl ether. The
1-(4-Acetoxy-3-methoxy[phenyl-(U)-14C])-prop-1-yl acetate (8)
Diethyl ether (10 ml) was added to 1-(4′-hydroxy-3′-methoxy[phenyl-
(U)-14C])-propan-1-ol (0.451 g, 2.47 mmoles, 74.2 mCi) in a 50 ml flask. A
septum was placed on the flask with a needle connected to a dry
nitrogen bubbler. The flask was cooled in an ice bath, and triethylamine
(0.968 g, 9.57 mmoles) was added by syringe. To the resulting yellow
solution was added dropwise acetyl chloride (0.683 g, 8.70 mmoles) over
5 min. The mixture was stirred in the ice bath for 2 h; then water (20 ml)
was added. The mixture was stirred for 2 min; then the water layer was
bulk of the solvents were removed using a rotary evaporator; then the removed and the ether phase washed again with water (10 ml). The ether
product was placed under high vacuum to remove all traces of solvent.
GC analysis showed the product to be 99.2% pure, thus producing
0.766 g, (4.20 mmoles, 126 mCi, 95.4% yield) of a colorless liquid. 1H
NMR (CD3COCD3) δ 7.23–7.17 (m, 1H, aromatic), 7.09–7.02 (m, 2H,
aromatic), 6.96–6.90 (m, 1H, aromatic), 3.79 (s, 3H, methoxy), 2.57 (q,
J = 7.6 Hz, 2H, CH2), 1.19 (t, J = 7.5 Hz, 3H, CH3).
solution was dried over magnesium sulfate. The diester was purified by
flash chromatography using 3:1 hexane : ethyl acetate to produce
0.542 g (2.02 mmoles, 60.6 mCi, 81.6% yield) of product isolated as a
colorless oil. 1H NMR (CDCl3), δ 7.01 (d, J = 7.2 Hz, 1H, phenylacetate-
ortho), 6.92–6.90 (m, 2H, phenylacetate-meta), 5.65 (t, J = 6.9 Hz, 1H,
benzyl), 3.84 (s, 3H, methoxy), 2.31 (s, 3H, C6H3OCOCH3), 2.08 (s, 3H,
CH-OCOCH3), 1.91–1.80 (m, 2H, CH2), 0.90 (t, J = 7.4 Hz, 3H, CH3).
4′-Hydroxy-3′-methoxypropiophenone, [ring-(U)-14C] (6)
1-Phenylpropyl acetate (8a)
In a 25 ml two-neck flask was placed anhydrous aluminum chloride (1.232 g,
9.24 mmoles) and nitrobenzene (5 ml, dried with 4A sieves). A septum was
placed on the side neck, and a 10 cm glass extension tube with a CaSO4
drying tube was placed on the center neck. The mixture was gently heated
with a heat gun until the aluminum chloride dissolved. The flask was then
1-Phenyl-1-propanol (0.681 g, 5.00 mmoles) was dissolved in dichloromethane
(10 ml) in a 50 ml flask with a septum and needle connected to a dry
nitrogen bubbler. The mixture was cooled in an ice bath, and triethylamine
(0.506 g, 7.50 mmoles) was added. Acetyl chloride (0.589 g, 7.50 mmoles)
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J. E. Immoos Jr.
was then added by syringe slowly over 3 to 5 min. The mixture was stirred (10 ml). The solution was dried with MgSO4 and then stripped to a light
at room temperature for 3 h and then placed back in the ice bath and yellow oil. The product was purified by flash chromatography using 4:1
quenched with water (15 ml). The dichloromethane layer was removed, hexane : ethyl acetate and was placed under vacuum to constant weight
and the aqueous layer extracted with dichloromethane (10 ml × 2). The to give 0.795 g of a colorless oil (2.68 mmoles, 89.4% yield). The product
dichloromethane solution was dried with MgSO4, and the product was
purified by flash chromatography using 4:1 pentane : diethyl ether to give connected to a dry nitrogen bubbler. Triethylamine (0.434 g, 4.29 m-
0.771 g of a colorless oil (4.33 mmoles, 86.5% yield). 1H NMR (CD2Cl2), δ
moles) was added, and the mixture was cooled in an ice bath. Acetyl
7.31–7.26 (m, 4H, aromatic), 5.60 (t, J = 6.8 Hz, 1H, benzyl), 2.02 (s, 3H, CH- chloride (0.316 g, 4.02 mmoles) was added dropwise by syringe over 3–
was dissolved in ether (6 ml) in a 50 ml flask with a septum and needle
OCOCH3), 1.94–1.73 (m, 2H, CH2), 0.86 (t, J = 7.2 Hz, 3H, CH3).
5 min. The mixture was stirred at room temperature for 2 h; then the
triethylamine hydrochloride was filtered and washed with ether. The
ether was removed and the product purified by flash chromatography
using 6:1 hexane : ethyl acetate to produce 0.877 g (2.59 mmoles, 96.6%
yield) of a colorless oil. The resulting product was dissolved in THF
(7 ml) in a 25 ml flask. Triethylamine trihydrofluoride (0.418 g, 2.59 m-
moles) was added, and the mixture was stirred at room temperature
for 2.5 h. The THF was removed by rotovap, and the residue was
dissolved in ether (15 ml). The ether solution was washed with saturated
sodium bicarbonate (6 ml). The sodium bicarbonate wash was back
extracted with ether (10 ml × 2). The combined ether solutions were
dried with MgSO4 and the ether removed leaving a light yellow oil. The
product was purified by flash chromatography using 2:1 hexane : ethyl
acetate to produce 0.517 g (2.31 mmoles, 89% yield) of a colorless oil. 1H
NMR (CD2Cl2), δ 6.85–6.82 (m, 3H, aromatic), 5.74 (s, 1H, OH), 5.41 (t,
J = 7.2 Hz, 1H, benzyl), 3.87 (s, 3H, methoxy), 2.03 (s, 3H, CH-OCOCH3),
1.93–1.73 (m, 2H, CH2), 0.86 (t, J = 7.2 Hz, 3H, CH3).
1-(Benzo[d]dioxol-5-yl)propyl acetate (8b)
3,4-Methylenedioxypropiophenone (0.353 g, 3.00 mmoles) was dissolved
in 2-propanol (6 ml), and sodium borohydride (0.136 g, 3.60 mmoles) was
added. The mixture was stirred at room temperature for 18 h. The solvent
was removed on the rotovap; then the flask was cooled in an ice bath,
and water (10 ml) was added to dissolve the residue. The product was
extracted with ether (3 × 10 ml) and the extracts dried with MgSO4. The
ether was evaporated to produce a colorless oil. The oil was purified by
flash chromatography using 4:1 hexane : ethyl acetate to produce
0.525 g of product (2.91 mmoles, 97.1% yield). The product was dissolved
in dichloromethane (6 ml), and triethylamine (0.442 g, 4.37 mmoles) was
added. A septum with a needle connected to a dry nitrogen bubbler
was attached, the mixture was cooled in an ice bath, and acetyl chloride
(0.343 g, 4.37 mmoles) was added dropwise over 2–3 min. The mixture
was then stirred at room temperature for 5 h. The flask was then again
cooled in an ice bath and quenched with water (15 ml). The
dichloromethane layer was removed, and the aqueous layer was
extracted with dichloromethane (10 ml × 2). The product solution
was dried with MgSO4 and purified by flash chromatography using
4:1 hexane : ethyl acetate to produce 0.476 g of a colorless oil
(2.14 mmoles, 73.5% yield). 1H NMR (CD2Cl2), δ 6.82 (s, 1H, aromatic),
6.80–6.74 (m, 2H, aromatic), 5.92 (s, 2H, O-CH2-O), 5.51 (t, J = 6.8 Hz,
1H, benzyl), 2.02 (s, 3H, CH-OCOCH3), 1.92–1.69 (m, 2H, CH2), 0.85
(t, J = 7.2 Hz, 3H, CH3).
4-(1-Acetoxypropyl)-2-methoxyphenyl benzoate (8e)
1-(4′-Hydroxy-3′-methoxyphenyl)-prop-1-ol (0.547 g, 3.00 mmoles) was
dissolved in diethyl ether (6 ml) in a 50 ml flask with a septum and needle
connected to a dry nitrogen bubbler. Triethylamine (0.455 g, 4.50 m-
moles) was added, and the flask was cooled in an ice bath. Benzoyl
chloride (0.633 g, 4.50 mmoles) was then added dropwise over 5 min.
The reaction mixture was stirred in the ice bath for 2.5 h and then
quenched with water (20 ml). The ether layer was removed, and the
aqueous layer was extracted with ether until all solid dissolved
(10 ml × 6). After drying over MgSO4, the ether was removed by rotovap
to give a white solid, which was dried under vacuum for 16 h. The
product was purified by flash chromatography with 4:1 benzene : ethyl
acetate to produce 0.785 g (2.74 mmoles, 91.4% yield) of the product as
a white solid. To the resulting solid in a 50 ml flask, benzene (20 ml)
was added. Triethylamine (0.416 g, 4.11 mmoles) was then added, and
the reaction mixture cooled in an ice bath. A septum was attached to
the flask and acetyl chloride (0.323 g, 4.11 mmoles) was added slowly
over 2 to 3 min. The mixture was then stirred at room temperature for
3.5 h. The mixture was cooled in an ice bath and quenched with water
(10 ml). The organic layer was removed, and the aqueous layer was
extracted with ether (10 ml × 2). The organic solution was dried with
MgSO4 and then stripped to an orange oil. The product was placed under high
vacuum for 2 h. Purification by flash chromatography using 3:1 hexanes :
ethyl acetate produced 0.857 g (2.61 mmoles, 95.2% yield) of product as a
white solid. 1H NMR (CD2Cl2), δ 8.17 (d, J = 7.2 Hz, 2H, benzoyl-ortho), 7.65
(t, J = 7.2 Hz, 1H, benzoyl-para), 7.52 (t, J = 7.2 Hz, 2H, benzoyl-meta), 7.11
(d, J = 7.6 Hz, 1H, Bz-O-Ph-ortho), 6.99-6.95 (m, 2 H, Bz-O-Ph-meta), 5.63 (t,
J = 6.4 Hz, 1H, benzyl), 3.81 (s, 3H, methoxy), 2.08 (s, 3H, CH-OCOCH3),
1.97–1.82 (m, 2H, CH2), 0.92 (t, J = 6.8 Hz, 3H, CH3).
1-(4-Methoxyphenyl)prop-1-yl acetate (8c)
4′-Methoxypropiophenone (0.493 g, 3.00 mmoles) was dissolved in 2-pro-
panol (6 ml) in a 50 ml flask. Sodium borohydride (0.136 g, 3.60 mmoles)
was added, and the mixture was stirred at room temperature for 26 h.
The 2-propanol was removed by rotovap and the flask cooled in an ice
bath. Water (10 ml) was added to dissolve the residue, and the product
was extracted with ether (10 ml × 3). After drying with MgSO4, the ether
was removed and the product purified by flash chromatography using
2:1 hexane : ethyl acetate to produce 0.492 g (2.96 mmoles, 98.7% yield)
of a colorless oil. This product was then dissolved in dichloromethane
(6 ml) and triethylamine (0.449 g, 4.44 mmoles) added. The mixture was
placed under a dry nitrogen atmosphere, cooled in an ice bath, and
acetyl chloride (0.349 g, 4.44 mmoles) was added slowly over 2 to 3 min
by syringe through a septum. The mixture was stirred at room
temperature for 2 h and then cooled again in the ice bath. The reaction
was quenched with water (10 ml) and the product extracted with
dichloromethane (10 ml × 2). The solution was dried with MgSO4 and
purified by flash chromatography using 4:1 hexane : ethyl acetate to
produce 0.482 g (2.32 mmoles, 78.2%) of product as a colorless oil. 1H
NMR (CD2Cl2), δ 7.24 (d, J = 8 Hz, 2H, methoxyphenyl-meta), 6.86 (d,
J = 8 Hz, 2H, methoxyphenyl-ortho), 5.56 (t, J = 6.8 Hz, 1H, benzyl), 3.77
(s, 3H, methoxy), 2.01 (s, 3H, CH-OCOCH3), 1.94–1.71 (m, 2H, CH2), 0.85
(t, J = 7.6 Hz, 3H, CH3).
4-(1-Acetoxypropyl)-2-methoxyphenyl pivalate (8f)
To 1-(4′-hydroxy-3′-methoxyphenyl)-prop-1-ol (0.547 g, 3.00 mmoles) in a
50 ml flask with a septum and needle to a dry nitrogen bubbler was added
diethyl ether (9 ml). Triethylamine (0.455 g, 4.50 mmoles) was added, and
the mixture was cooled in an ice bath. Pivaloyl chloride (0.543 g,
4.50 mmoles) was added slowly over 2 to 3 min; then the mixture was
stirred in the ice bath for 5 h. The reaction mixture was cooled in an ice
1-(4-Hydroxy-3-methoxyphenyl)prop-1-yl acetate (8d)
1-(4-Hydroxy-3-methoxyphenyl)propan-1-ol (0.547 g, 3.00 mmoles) was
dissolved in benzene (12 ml) in a 50 ml flask. To this was added tert-
butyldimethylchlorosilane (0.513 g, 3.30 mmoles) and 1,8-diazabicy- bath and quenched with water (10 ml). The ether layer was removed,
clo[5.4.0]undecene, DBU (0.548 g, 3.60 mmoles), and the mixture was and the aqueous layer was extracted with ether (10 ml × 2). The ether
stirred at room temperature for 2 h. The hydrochloride salt of the DBU
was filtered and washed with benzene (10 ml). The benzene solution
was washed with 0.1 N HCl (10 ml) and saturated sodium bicarbonate
solution was dried with MgSO4 and the ether removed to produce a
slightly orange oil. Purification by flash chromatography with 2:1 he-
xanes : ethyl acetate produced 0.748 g (2.81 mmoles, 93.6% yield) of a
J. Label Compd. Radiopharm 2015, 58 419–424
Copyright © 2015 John Wiley & Sons, Ltd.
www.jlcr.org

J. E. Immoos Jr.
colorless oil. The oil was dissolved in diethyl ether (10 ml), and triethy-
lamine (0.426 g, 4.21 mmoles) was added. A septum with a needle to a
bromide (3 M in diethyl ether, 8 ml, 24.00 mmoles) was added dropwise
over 15 min. The reaction mixture was stirred 2 h in the ice bath and then
dry nitrogen bubbler was placed on the flask and the flask cooled in an quenched by the slow addition of water (10 ml). The THF was removed
ice bath. Acetyl chloride (0.331 g, 4.21 mmoles) was added slowly over 2
to 3 min; then the mixture was stirred at room temperature for 6 h. The
reaction mixture was again cooled in an ice bath and quenched with
water (10 ml). The ether phase was removed, and the aqueous phase
was extracted with ether (10 ml × 2). The ether solution was dried with
MgSO4 and the ether removed to produce a slightly yellow oil. Purifi-
on the rotovap, and water (10 ml) was added to dissolve the residue.
The pH was adjusted to 1 to 2 with 2 N HCl, and the product was
extracted with diethyl ether (10 ml × 4). The ether solution was washed
with saturated sodium bicarbonate (10 ml) and dried with MgSO4, and
the product was purified by flash chromatography using 1:1 hexane :
ethyl acetate to give 1.464 g of a white solid (8.03 mmoles, 80.3% yield).
cation by flash chromatography using 2:1 hexanes : ethyl acetate pro- 1H NMR matches that of [14C] 7.
duced 0.748 g (2.43 mmoles, 80.9% yield) of a colorless oil. 1H NMR
(CD2Cl2), δ 6.96–6.89 (m, 3H, aromatic), 5.60 (t, J = 6.8 Hz, 1H, benzyl),
3.80 (s, 3H, methoxy), 2.06 (s, 3H, CH-OCOCH3), 1.94–1.77 (m, 2H, CH2),
1.34 (s, 9H, C(CH3)3), 0.90 (t, J = 7.2, 3H, CH3).
Conclusion
Isoeugenol, [ring-(U)-14C] has been synthesized by a novel, 10
1-(4′-Acetoxy-3′-methoxy[phenyl-(U)-14C])-prop-1-ene (9)
step sequence starting from 14C labeled phenol. The generation
of the unsaturated function in the side chain is suggested to
occur via a quinone methide intermediate.
To 1-(4′-acetoxy-3′-methoxy[phenyl-(U)-14C])-prop-1-yl acetate (0.542 g,
2.02 mmoles, 60.6 mCi) in a 25 ml flask was added dimethylformamide
(3 ml) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (0.338 g, 2.22 mmoles).
The mixture was heated to 80 °C for 2 h and then cooled to room
temperature and added to 30 ml of water cooled in an ice bath. The
product was extracted with ether and dried over magnesium sulfate.
Thin layer chromatography (TLC) analysis on silica gel with 4:1 hexane :
ethyl acetate showed the product at Rf = 0.45 and a second product at
Rf = 0.40 co-eluting with isoeugenol standard. Gas chromatography
showed that the product consisted of a mixture of 88% monoacetate
product, 9, and 12% isoeugenol. The mixture was purified on silica gel
using 4:1 hexane : ethyl acetate with the two products being collected
together. A total of 0.388 g of the combined products was recovered
Acknowledgements
The author would like to thank Dr. Paula Francom for her
suggestions for the mechanism study, NMR assignments, and
organization of this paper.
and used directly in the final step. 1H NMR (CD2Cl2) for the purified Conflict of interest
monoacetate δ 6.94–6.87 (m, 3H, aromatic), 6.38 (d, J = 15.6 Hz, 1H,
benzyl), 6.27–6.13 (m, 1H, C6H3CH = CH), 3.81 (s, 3H, methoxy), 2.29 (s,
3H, OCOCH3), 1.87 (d, J = 6.4 Hz, 3H, CH = CH-CH3).
The authors did not report any conflict of interest.
Isoeugenol, [ring-(U)-14C] (10)
References
To the mixture of 0.388 g of 1-(4′-acetoxy-3′-methoxy[phenyl-(U)-14C])-
prop-1-ene (88%,1.65 mmoles) and isoeugenol, [ring-(U)-14C] (12%, 0.28 -
mmoles) in a 25 ml flask was added 4 ml sodium methoxide (25 wt% in
methanol). The mixture was stirred at room temperature for 2 h. The
methanol was removed under vacuum using a rotary evaporator. Ice
water (15 ml) was added to the residue, and the mixture was stirred. After
5 min, a precipitate was formed. The mixture was washed twice with 8 ml
of ether. The mixture was then acidified to pH of 3–4 with concentrated
hydrochloric acid while cooling in an ice bath. The product was extracted
with ether (10 ml × 3), the ether solution washed with saturated sodium
bicarbonate (10 ml) and dried over magnesium sulfate. TLC analysis on
silica gel using 4:1 hexane : ethyl acetate showed a single spot at
Rf = 0.40 co-eluting with isoeugenol standard. The product was further
purified by flash chromatography using 4:1 hexane : ethyl acetate to
produce 0.194 g, (1.18 mmoles, 35.4 mCi, 58% yield from the diester) of
colorless oil. HPLC analysis showed the product to contain the cis
(retention time = 46.2 min) and trans (retention time = 48.2 min) isomers
of isoeugenol in a ratio of 3 to 97. 1H NMR (CD2Cl2), δ 6.79 (s, 2H,
aromatic), 6.87(s, 1H, aromatic), 6.30 (d, J = 15.6 Hz, 1H, benzyl), 6.04–
6.13 (m, 1H, C6H3CH = CH), 5.65 (s, 1H, OH), 3.85 (s, 3H, methoxy), 1.84
(d, J = 6.4 Hz, 3H, CH = CH-CH3).
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1-(4-Hydroxy-3-methoxyphenyl)propan-1-ol (11) (from vanillin and
EtMgBr)
Vanillin (1.522 g, 10.00 mmoles) was dissolved in THF (30 ml) in a 100 ml
flask. A septum was attached with a needle connected to a dry nitrogen
bubbler. The mixture was cooled in an ice bath, and ethylmagnesium
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Copyright © 2015 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2015, 58 419–424