Synthesis of 5-methoxymethyl, 5-(2-methoxyethyl), and 5-allyl thebaine, codeinone, and morphinone derivatives

Article abstract of DOI:10.1023/B:RUJO.0000010211.00822.24

Simple routes to 5-methoxymethylthebaine, 5-(2-methoxyethyl)thebaine, 5-allylthebaine, and similarly substituted codeinones and morphinones are described.

Full text of DOI:10.1023/B:RUJO.0000010211.00822.24

Russian Journal of Organic Chemistry, Vol. 39, No. 9, 2003, pp. 1256 1260. From Zhurnal Organicheskoi Khimii, Vol. 39, No. 9, 2003, pp. 1330 1334.
Original English Text Copyright 2003 by Lotfy, Schultz, Metwally.
Synthesis of 5-Methoxymethyl, 5-(2-Methoxyethyl), and 5-Allyl
Thebaine, Codeinone, and Morphinone Derivatives*
2
H. R. Lotfy1, A. G. Schultz , and M. A. Metwally3
1
El-Khiaria, El-Mansoura, Egypt
2
Department of Chemistry, RPI (Rensselaer Polytechnic Institute), Troy, New York, 12180-3590, USA
3
Department of Chemistry, Faculty of Science, University of Mansoura, Egypt
Received February 12, 2003
Abstract Simple routes to 5-methoxymethylthebaine, 5-(2-methoxyethyl)thebaine, 5-allylthebaine, and
similarly substituted codeinones and morphinones are described.
The goal of this work was to prepare a new series
of 5-substituted thebaine derivatives and convert them
into the corresponding codeinones and morphinones.
It was expected that the resulting morphine-like and
codeine-like compounds will show a reduced addic-
tion effect while keeping their analgetic effect.
Metalation of thebaine (I) at the C5 atom was
performed according to the known procedure [1], and
subsequent alkylation gave substrates which were then
converted into 5-substituted codeinone and morphi-
none derivatives. A solution of thebaine (I) in tetra-
hydrofuran was treated with 1.6 equiv of 2.5 M
n-butyllithium in hexane. Quenching of the resulting
solution with chloromethyl methyl ether afforded
5-methoxymethylthebaine (II) in 30% yield. Alkyla-
tion of the thebaine anion with 2-chloroethyl methyl
ether gave 5-(2-methoxyethyl)thebaine (III) (57.4%
on the reacted initial compound). 5-Allylthebaine (IV)
was synthesized in 80% yield by treatment of a solu-
tion containing thebaine anion with allyl chloride
(Scheme 1). Our attempts to convert 5-substituted
thebaines into 5-substituted codeinones with mercury
acetate were unsuccessful. Therefore, the oxidation
was carried out using peroxyformic acid on heating
(Scheme 2). It is known that the oxidation of 5-ben-
zylthebaine [2] with hydrogen peroxide in formic acid
[3] in 65 h at 0 C leads to 5-benzyl-14-hydroxycodei-
none (V) [2] in an improved yield (61%). By oxida-
tion of 5-methoxymethylthebaine (II) with a mixture
of formic acid and hydrogen peroxide at 4 C (70 h)
we obtained 5-methoxymethyl-14-hydroxycodeinone
(VI) in 62% yield. 5-(2-Methoxyethyl)-14-hydroxy-
codeinone (VII) and 5-allyl-14-hydroxycodeinone
(VIII) were synthesized in 60 and 85% yield, respec-
tively, by treatment of III and IV with hydrogen
peroxide in formic acid at 4 C (66 h).
It should be noted that the presence of a hydroxy
group in position 14 of the morphine skeleton was
reported [4 6] to advantageously influence pharmaco-
logical properties.
Scheme 1.
II, R = MeOCH2; III, R = MeOCH2CH2; IV, R = CH2 CHCH2.
____________
Deceased.
*
The original article was submitted in English.
1070-4280/03/3909-1256$25.00 2003 MAIK Nauka/Interperiodica

SYNTHESIS OF 5-METHOXYMETHYL, 5-(2-METHOXYETHYL), AND 5-ALLYL
1257
Scheme 2.
II, VI, R = MeOCH2; III, VII, R = MeOCH2CH2; IV, VIII, R = CH2=CHCH2; V, R = PhCH2 [2].
Scheme 3.
V, IX, R = PhCH2; VIII, X, R = CH2=CHCH2.
A solution of 5-benzyl-14-hydroxycodeinone (V)
in methylene chloride was treated with boron tri-
bromide at 20 C over a period of 20 h. The reaction
afforded 73% of 5-benzyl-14-hydroxymorphinone
(IX) (Scheme 3). All atempts to convert in such a way
compounds VI and VII into the corresponding mor-
phinones failed: the reaction with BBr3 resulted in
loss of the methoxy group from the substutent on C5.
Treatment of a solution of 5-allyl-14-hydroxycodei-
none (VIII) with BBr3 at room temperature (reaction
time 20 h) gave 67.5% of 5-allyl-14-hydroxymorphi-
none (X) (Scheme 3).
were determined on a Thomas Hoover capillary
melting point apparatus; corrected values are given.
5-Methoxymethylthebaine (II). A solution of 5 g
of thebaine in 250 ml of tetrahydrofuran was placed
in a flame-dried round-bottom flask, and 9.64 ml
(1.5 equiv) of a 2.5 M solution of n-butyllithium in
hexane was added with stirring at 78 C under nitro-
gen. The mixture immediately turned deep wine-red.
It was stirred for 20 min at 78 C, 1.83 ml of chloro-
methyl methyl ether was added, and the mixture was
stirred for 20 min at 78 C, allowed to warm up to
room temperature, and left overnight. The color
changed to yellow. Distilled waster, 5.0 ml, was
added dropwise, and most part of the solvent was
removed under reduced pressure. The brown residue
was dissolved in chloroform, and the solution was
washed with two portions of water, filtered through
anhydrous magnesium sulfate, and concentrated. The
residue was subjected to chromatography on silica gel
using chloroform methanol (2:1) as eluent. Yield
30%. Recrystallization from hexane gave green crys-
Photochemical properties of the prepared codeinone
and morphinone derivatives will be the subject of
a separate communication.
EXPERIMENTAL
1
The H NMR spectra were recorded on Varian
EX-200 (200 MHz) and Unity 500 (500 MHz) spec-
trometers using chloroform-d as solvent and internal
reference. The 13C NMR spectra were obtained with
and without decoupling from protons on a Unity 500
instrument (500 MHz) using chloroform as solvent
and internal reference. The IR spectra were measured
on a Perkin Elmer Model 298 or FTIR spectrometer.
The chemical ionization mass spectra were obtained
on a Hewlett Packard 5987A GC MS system using
isobutene as chemical ionization gas. Elemental
analysis was performed at Quantitative Technologies
Inc. Laboratories, Whitehouse, NJ. The melting points
1
tals with mp 126 128 C. H NMR spectrum (CDCl3),
, ppm: 6.65 d (1H, J = 8.3 Hz), 6.59 d (1H, J =
8.1 Hz), 5.57 d (1H, J = 6.6 Hz), 5.19 d (1H, J =
6.4 Hz), 4.14 d (1H, J = 9.2 Hz), 3.82 s (3H, OMe),
3.82 d (1H, J = 9.2 Hz), 3.62 d (1H, J = 5.4 Hz),
3.59 s (3H), 3.36 s (3H, OMe), 3.25 d (1H, J =
17.6 Hz), 2.45 2.9 m (4H), 2.45 s (3H, NMe),
1.67 d.d (1H, J = 2.2, 2.4 Hz). IR spectrum (CDCl3),
1
, cm : 2910, 2820, 2240, 1600, 1490, 1440, 1271,
1227, 1100, 1048, 905, 725. Mass spectrum (CI), m/z
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

1258
LOTFY et al.
(Irel, %): 356 (M+ + 1, 100), 355 (23), 324 (4), 310
(2). Found, %: C 71.37; H 7.10; N 3.95. C21H25NO4.
Calculated, %: C 70.98; H 7.04; N 3.94. M 355.
yellow brown residue was dissolved in chloroform,
and the solution was washed with two portions of
water, filtered through anhydrous magnesium sulfate,
and concentrated. The residue was subjected to
chromatography on silica gel using methanol chloro-
form (1:9) as eluent. Yield 4.00 g (80%). The product
was recrystallized from hexane. Yellow brown crys-
5-(2-Methoxyethyl)thebaine (III). A 2.5 M solu-
tion of n-butyllithium in hexane, 10 ml, was added
with stirring at 78 C under nitrogen to a solution
of 5.00 g of thebaine in 250 ml of tetrahydrofuran
(freshly distilled over sodium diphenylketyl). The
mixture immediately turned deep wine-red. It was
stirred for 25 min at 78 C, 2.2 ml (1.5 equiv) of
freshly distilled 2-chloroethyl methyl ether was added,
and the mixture was stirred for 30 min at 78 C,
allowed to warm up to room temperature, and left
overnight. The color changed to orange yellow.
Water, 5.00 ml, was added, and most part of the
solvent was removed under reduced pressure. The
yellow brown residue was dissolved in methylene
chloride, and the solution was washed with two
portions of water, filtered through anhydrous magne-
sium sulfate, and concentrated. The residue was sub-
jected to chromatography on silica gel using MeOH
CH2Cl2 (1:9) as eluent to isolate 2.01 g of compound
III as a pale yellow oil (57.4%, calculated on the
reacted thebaine) and 1.5 g of the initial compound.
1H NMR spectrum (CDCl3, 500 MHz), , ppm:
1.69 d.d (1H, J = 2.4, 2.2 Hz), 2.23 2.35 m (3H),
2.46 s (3H, NMe), 2.62 2.80 m (4H), 3.28 d (1H,
J = 17.6 Hz), 3.31 s (3H, OMe), 3.46 m (1H), 3.56 s
(3H, OMe), 3.64 d (1H, J = 6.6 Hz), 3.83 s (3H,
OMe), 5.04 d (1H, J = 6.5 Hz), 5.55 d (1H, J =
6.4 Hz), 6.58 d (1H, J = 8.1 Hz), 6.63 d (1H, J = 8.3).
13C NMR spectrum (CDCl3, 500 MHz), C, ppm:
154.48, 143.45, 142.59, 134.63, 132.30, 127.13,
119.38, 112.60, 112.30, 96.53, 94.47, 68.81, 61.65,
58.86, 56.23, 54.99, 47.42, 45.82, 42.48, 33.06,
1
tals, mp 104 105 C. H NMR spectrum (CDCl3), ,
ppm: 6.63 d (1H, J = 8.3 Hz), 6.55 d (1H, J = 8 Hz),
5.7 m (1H), 5.53 d (1H, J = 6.6 Hz), 5.16 m (3H),
3.85 d (1H, J = 5.8 Hz), 3.85 s (3H), 3.62 d (1H, J =
8 Hz), 3.56 s (3H), 3.24 m (2H), 2.57 2.93 m (4H),
2.45 s (3H), 1.68 d.d (1H, J = 2.2, 2.4 Hz). 13C NMR
spectrum (CDCl3, 500 MHz), C, ppm: 154.18,
151.15, 143.41, 142.38, 134.66, 132.85, 132.05,
127.05, 119.18, 118.16, 112.30, 112.12, 95.31, 61.45,
56.07, 54.87, 47.25, 45.66, 42.36, 37.36, 30.34,
1
59.54. IR spectrum (CDCl3), , cm : 2920, 2220,
1598, 1493, 1435, 1271, 1220, 1100, 1049, 902. Mass
spectrum (CI), m/z (Irel, %): 352 (M+ + 1, 100), 336
(2), 310 (1), 295 (2), 216 (1). Found, %: C 75.28;
H 7.23; N 3.95. C22H25NO3. Calculated, %: C 75.21;
H 7.12; N 3.98. M 351.
5-Benzyl-14-hydroxycodeinone (V). An ice-cold
mixture of 1.2 ml of 0.7% H2SO4, 0.35 ml of 88%
HCO2H, and 0.7 ml of 30% H2O2 was added to
1.00 g (2.49 mmol) of 5-benzylthebaine. The mixture
was stirred at 0 C until it became transparent
( 30 min). The resulting solution was kept for 65 h
in a refrigerator (4 C) and poured into 20 ml of ice
water which was made alkaline by addition of a con-
centrated ammonia solution. The mixture was ex-
tracted with 5 portions of chloroform, and the organic
extracts were combined, dried over magnesium sul-
fate, and evaporated to obtain 0.61 g (61%) of 5-ben-
zyl-14-hydroxycodeinone (V). Recrystallization from
hexane gave off-white needles with mp 177 178 C.
1H NMR spectrum (CDCl3, 500 MHz), , ppm:
1.48 d.d (1H, J = 3.6, 3.5 Hz), 2.2 d.d.d (1H, J = 3.6,
3.9 Hz), 2.46 s (3H), 2.46 m (3H), 2.92 d (1H, J =
5.4 Hz), 3.17 d (1H, J = 18.3 Hz), 3.38 d (1H, J =
14.6 Hz), 3.6 d (1H, J = 14.6 Hz), 3.85 s (3H),
4.8 br.s (1H), 6.08 d (1H, J = 10 Hz), 6.51 d (1H,
J = 10 Hz), 6.57 d (1H, J = 8.3 Hz), 6.65 d (1H, J =
8.3 Hz), 7.26 m (5H). 13C NMR spectrum (CDCl3,
500 MHz), C, ppm: 198.12, 146, 143.56, 142.6,
135.24, 133.56, 131.42, 130.73, 127.85, 126.59,
124.64, 119.09, 114.72, 94.53, 68.16, 64.49, 56.71,
48.4, 45.35, 42.37, 37.46, 26.4, 22.44. IR spectrum
1
30.59, 29.86. IR spectrum (CDCl3), , cm : 2920,
1600, 1495, 1440, 1278, 1250, 1230, 1100, 1049,
1010, 905. Mass spectrum (CI), m/z (Irel, %): 370
(M+ + 1, 100), 368 (4), 312 (7), 310 (2). Found, %:
C 71.59; H 7.38; N 3.76. C22H27NO4. Calculated, %:
C 71.54; H 7.32; N 3.79. M 369.
5-Allylthebaine (IV). A 2.5 M solution of n-butyl-
lithium in hexane, 10 ml, was added with stirring at
78 C under nitrogen to a solution of 5.00 g of
thebaine in 300 ml of tetrahydrofuran (freshly distilled
over sodium diphenylketyl). The mixture immediately
turned deep wine-red. The mixture was stirred for
30 min at 78 C, 2 ml of freshly distilled allyl
chloride was added, and the mixture was stirred for
30 min at 78 C, allowed to warm up to room tem-
perature, and left overnight. The color changed to
yellow. Water, 5 ml, was added, and most part of the
solvent was removed under reduced pressure. The
1
(CHCl3), , cm : 3330, 1670. Mass spectrum (CI),
m/z (Irel, %): 404 (M+ + 1, 100), 386 (1), 319 (1), 298
(6). Found, %: C 74.37; H 6.34; N 3.41. C23H25NO4.
Calculated, %: C 74.44; H 6.2; N 3.47. M 403.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

SYNTHESIS OF 5-METHOXYMETHYL, 5-(2-METHOXYETHYL), AND 5-ALLYL
1259
14-Hydroxy-5-methoxymethylcodeinone (VI).
An ice-cold mixture of 0.65 ml of 0.7% H2SO4,
0.2 ml of 88% HCO2H, and 0.4 ml of 30% H2O2 was
added to 0.5 g (1.4 mmol) of 5-methoxymethylthe-
baine. The mixture was stirred at 0 C until it became
homogeneous ( 25 min), kept for 70 h in a refrigera-
tor (4 C), and poured into 5 ml of ice water which
was made alkaline by addition of a concentrated
ammonia solution. The mixture was extracted with
5 portions of chloroform, and the extracts were com-
bined, dried over magnesium sulfate, and evaporated
to obtain 0.31 g (62%) of 14-hydroxy-5-methoxy-
methylcodeinone (VI). Recrystallization from chloro-
5-Allyl-14-hydroxycodeinone (VIII). An ice-cold
mixture of 1.3 ml of 0.7% H2SO4, 0.4 ml of 88%
HCO2H, and 0.8 ml of 30% H2O2 was added to 1 g
(2.8 mmol) of 5-allylthebaine, and the mixture was
stirred at 0 C until it became homogeneous (20 min),
kept for 66 h in a refrigerator (4 C), and poured into
20 ml of ice water which was made alkaline (pH 9) by
addition of a concentrated ammonia solution. The
mixture was extracted with several portions of chloro-
form, and the organic extracts were combined, dried
over magnesium sulfate, and evaporated to isolate
compound VIII in 85% yield. Recrystallization from
hexane gave bright yellow needles with mp 147
1
form hexane (1:20) gave off-white crystals, mp 145
147 C. H NMR spectrum (CDCl3, 500 MHz),
149 C. H NMR spectrum (CDCl3), , ppm: 1.54 d.d
1
,
(1H, J = 2.2, 2.4 Hz), 2.32 d.d.d (1H, J = 3.53, 3.48,
3.61 Hz), 2.42 2.56 m (3H), 2.45 s (3H, NMe),
2.82 d.d (1H, J = 6.68, 6.63 Hz), 3.04 d (1H, J =
8.06 Hz), 3.15 d.d (1H, J = 6.7, 6.68 Hz), 3.22 d
(1H, J = 18.3 Hz), 3.82 s (3H, 3-OMe), 5.11 m (3H),
6.11 d (1H, J = 10 Hz), 6.11 m (1H), 6.54 d (1H, J =
9.89 Hz), 6.62 d (1H, J = 8.18 Hz), 6.67 d (1H, J =
ppm: 1.56 d.d (1H, J = 2.2, 2.4 Hz), 2.2 2.4 m (4H),
2.44 s (3H, NMe), 3.15 d (1H, J = 5.2 Hz), 3.25 d
(1H, J = 18.6 Hz), 3.42 s (3H, OMe), 3.81 s (3H,
3-OMe), 3.94 d (1H, J = 8.5 Hz), 4.12 d (1H, J =
8.5 Hz), 4.3 br.s (1H), 6.07 d (1H, J = 10.2 Hz),
6.65 m (3H). 13C NMR spectrum (CDCl3, 500 MHz),
C, ppm: 196.85, 148.98, 142.98, 142.65, 132.22,
131.46, 125.53, 119.73, 114.14, 90.79, 70.12, 67.92,
62.84, 59.89, 56.45, 48.32, 45.76, 42.57, 25.32,
8.2 Hz). 13C NMR spectrum (CDCl3, 500 MHz),
,
C
ppm: 197.85, 146.25, 143.57, 142.53, 134.23, 131.75,
131.48, 124.76, 119.11, 118.59, 114.16, 94.01, 68.02,
64.63, 56.48, 47.99, 45.27, 42.43, 35.88, 26.27,
1
22.27. IR spectrum (CHCl3), , cm : 3410, 1670.
Mass spectrum (CI), m/z (Irel, %): 358 (M+ + 1, 100),
328 (4), 314 (30). Found, %: C 67.22; H 6.50; N 3.89.
C20H23NO5. Calculated, %: C 67.22; H 6.44; N 3.92.
22.37. IR spectrum (CHCl3), , cm : 3330, 1673.
1
Mass spectrum (CI), m/z (Irel, %): 354 (M+ + 1, 100),
336 (6), 314 (3), 269 (2), 217 (3). Found, %: C 71.13;
H 6.62; N 3.96. C21H23NO4. Calculated, %: C 71.38;
H 6.51; N 3.96. M 353.
14-Hydroxy-5-(2-methoxyethyl)codeinone (VII).
An ice-cold mixture of 1.6 ml of 0.7% H2SO4,
0.50 ml of 88% HCO2H, and 1.0 ml of 30% H2O2
was added to 1.3 g (3.5 mmol) of 5-(2-methoxyethyl)-
thebaine. The mixture was stirred at 0 C until it
became homogeneous ( 15 min), kept for 60 h in
a refrigerator (4 C), and poured into 20 ml of ice
water which was made alkaline (pH 9) by addition of
a concentrated ammonia solution. It was then extracted
with several portions of methylene chloride, the
extracts were combined and dried over MgSO4, and
the solvent was removed to obtain 0.78 g (60%) of
14-hydroxy-5-(2-methoxyethyl)codeinone (VII) as
a pale green oil. 1H NMR spectrum (CDCl3,
500 MHz), , ppm: 1.51 d.d (1H, J = 2.4, 2.2 Hz),
2.17 2.42 m (3H), 2.44 s (3H, NMe), 2.47 2.69 m
(3H), 3.00 d (1H, J = 5.6 Hz), 3.2 d (1H, J =
18.6 Hz), 3.26 s (3H, OMe), 3.65 m (1H), 3.79 m
(1H), 3.82 s (3H, OMe), 5.2 br.s (1H), 6.12 d (1H,
J = 10 Hz), 6.53 d (1H, J = 10.2 Hz), 6.59 d (1H,
J = 8.3 Hz), 6.65 d (1H, J = 8 Hz). IR spectrum
5-Benzyl-14-hydroxymorphinone (IX). A 25-ml
flame-dried round-bottom flask was charged with
20 mg (0.049 mmol) of 5-benzylcodeinone and 3 ml
of freshly distilled methylene chloride (preliminarily
dried over calcium hydride). The solution was cooled
in a cryogenic bath to 12 C under nitrogen, 0.04 ml
(0.42 mmol) of boron tribromide was added, and the
mixture was stirred for 20 h at 12 C. Methanol,
0.5 ml, was then added, and the mixture was treated
with a saturated solution of NaHCO3 and extracted
with methylene chloride. The aqueous layer was
thoroughly extracted with a mixture of methylene
chloride with ethanol (3:2), and the extracts were
combined, dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The residue
was 5-benzylmorphinone hydrobromide. It was dis-
solved in methanol, and the solution was treated with
a solution of NaHCO3. The free base was extracted
into methylene chloride, the extract was dried over
anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure to obtain 14.6 mg
(73%) of compound IX as a green foam-like material.
1H NMR spectrum, , ppm: 1.50 d.d (1H, J = 3.7,
1
(CDCl3), , cm : 3340, 1678. Mass spectrum (CI),
m/z (Irel, %): 372 (M+ + 1, 100), 356 (4), 340 (5), 314
(22). Found, %: C 67.96; H 6.79; N 3.78. C21H25NO5.
Calculated, %: C 67.92; H 6.74; N 3.77. M 371.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

1260
LOTFY et al.
3.5 Hz), 2.25 m (1H), 2.44 s (3H, NMe), 2.5 m (3H),
2.96 d (1H, J = 4.7 Hz), 3.18 d (1H, J = 18.5 Hz),
3.35 d (1H, J = 14.9 Hz), 3.56 d (1H, J = 14.6 Hz),
5.2 br.s (2H), 6.08 d (1H, J = 10.3 Hz), 6.55 m (2H),
6.66 d (1H, J = 8.3 Hz), 7.28 m (5H). IR spectrum
(3H), 2.44 s (3H, NMe), 2.83 d.d (1H, J = 6.4,
6.4 Hz), 3.01 m (2H), 3.19 d (1H, J = 18.6 Hz),
5.11 5.15 m (2H), 6.05 6.15 m (1H), 6.11 d (1H,
J = 9.8 Hz), 6.57 m (2H), 6.67 d (1H, J = 8.3 Hz).
13C NMR spectrum (CDCl3, 500 MHz), C, ppm:
198.70 (C O), 146.97, 142.02, 138,57, 133.83,
131.55, 130.88, 124.09, 119.70, 118.87, 117.64,
94.44, 68.16, 64.64, 48.23, 45.30, 42.46, 35.89,
1
(CHCl3), , cm : 3320 br, 1675. Mass spectrum (CI),
m/z (Irel, %): 390 (M+ + 1, 100), 372 (6), 351 (5), 300
(2). Found, %: C 73.96; H 5.97; N 3.56. C24H23NO4.
Calculated, %: C 74.04; H 5.91; N 3.60. M 389.
1
26.22, 22.43. IR spectrum (CHCl3), , cm : 3340 br,
1672. Mass spectrum (CI), m/z (Irel, %): 340 (M+ + 1,
100), 322 (2), 299 (2), 250 (1). Found, %: C 70.86;
H 6.15; N 4.19. C20H21NO4. Calculated, %: C 70.79;
H 6.19; N 4.13.
5-Allyl-14-hydroxymorphinone (X). A solution of
200 mg (0.567 mmol) of 5-allyl-14-hydroxycodeinone
in 2 ml of methylene chloride was added to a 1 M so-
lution of boron tribromide in methylene chloride
(1.1 ml, 11.6 mmol). The mixture was stirred for 20 h
at room temperature and poured into 20 ml of an ice-
cold dilute ammonia solution. The resulting mixture
was stirred for 30 min at 0 C. The aqueous layer was
separated, and the organic phase was extracted with
10 ml of a 1 M solution of sodium hydroxide. The
aqueous layers were combined and adjusted to pH 9.5
by adding a solution of NaOH. The solution was then
saturated with sodium chloride and extracted with
several portions of methylene chloride. The organic
extracts were combined and dried over magnesium
sulfate, and the solvent was removed under reduced
pressure to isolate 135 mg (67.5%) of a yellow oil
The authors thank the World Laboratory of
Switzerland for some financial support.
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1
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istic methoxy group proton signal at
3.82 ppm.
During drying some yellow crystals formed sponta-
1
neously. mp 199 201 C. H NMR spectrum (CDCl3,
500 MHz), , ppm: 1.54 d.d (1H, J = 2.7, 2.7 Hz),
2.27 d.d.d (1H, J = 3.7, 3.6, 3.6 Hz), 2.41 2.57 m
6. Ninan, A. and Sainsbury, M., Tetrahedron, 1992,
vol. 48, p. 6709.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003