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#137 MP
METAPROSCALINE; 3,4-DIMETHOXY-5-(n)-PROPOXYPHENETHYLAMINE
SYNTHESIS: There was mixed 96 g of 5-
bromovanillin and 90 mL 25%
NaOH.
The
solution was almost complete, when there was a sudden
deposition
of a heavy
precipitate. This was diluted with 200 mL water. There
was then added 300 mL
methylene chloride, 85 g
methyl iodide, and 3 g
decyltriethylammonium chloride. The
heterogenous mixture was
vigorously stirred for 2 days. The organic
phase was separated, and
the aqueous
phase extracted once with 100 mL
CH2Cl2. The organic
phase and extract were pooled, washed with water and the
solvent
removed under vacuum The residue weighed 46.3 g and spontaneously
crystallized. It was recrystallized from 40 mL of MeOH to yield 34 g
of
3-bromo-4,5-dimethoxybenzaldehyde as white
crystals with a mp of
60.5-61 °C. An additional 4 g product was obtained from the mother
liquor.
Acidification of the aqueous
phase above produced, after
re
crystalization from IPA/
acetone, 13.2 g of recovered
5-bromo-
vanillin, with a mp of 166-169 °C.
A mixture of 38.7 g
3-bromo-4,5-dimethoxybenzaldehyde and 17.2 g
cyclohexylamine was heated with an open flame at about 120 °C until it
appeared to be free of H2O. The residue was put under a vacuum (0.2
mm/
Hg) and
distilled at 146-160 °C yielding 44.6 g
3-bromo-N-
cyclohexyl-4,5-
dimethoxybenzylidenimine as a clear oil which
did not
crystallize. The imine stretch in the infra-red was at 1640
cm-1. Anal. (
C15H20BrNO2) C,H.
A
solution of 31.6 g 3-bromo-N-
cyclohexyl-4,5-
dimethoxybenzylidenimine
in 300 mL
anhydrous Et2O was placed in an
atmosphere of He, stirred
magnetically, and cooled with an dry ice/
acetone bath. Then 71 mL of
a 1.55 M
solution of
butyllithium in hexane was added over a 2 min
period. The reaction mixture turned cloudy and a light
precipitate
formed which seemed heaviest at the half-way point. Stirring remained
easy and was continued for 10 min. There was then added 35 mL of
butyl
borate at one time. The
precipitate dissolved, and the stirred
solution allowed to return to room tem
perature. There was then added
200 mL of an aqueous
solution containing 20 g
ammonium sulfate. The
Et2O layer was separated, washed with saturated
ammonium sulfate
solution, and the organic
solvents removed under vacuum. The residue
was
dissolved in 250 mL of 70% MeOH and 14 mL of 30% hydrogen
peroxide
added in small portions. This reaction was very exothermic, and
stirring was continued for 1 h. The reaction mixture was then added
to 500 mL H2O, which knocked out white solids. A small sample of this
intermediate, N-
cyclohexyl-
3,4-dimethoxy-5-
hydroxybenzylidineimine was
re
crystallized from MeOH to a white crystal with a mp of 148-149 °C
and which showed the C=N bond as a doublet at 1635 and 1645 cm-1 in
the infra-red. These wet solids were suspended in 200 mL 5% HCl and
heated on the steam bath for 1 h. Stirring was continued until the
reaction was again at room tem
perature and then it was extracted with
2x100 mL
CH2Cl2. These extracts were pooled and in turn extracted
with 2x75 mL dilute
NaOH. The aqueous extracts were reacidified with
HCl, and reextracted with 2x100 mL
CH2Cl2. These extracts were
pooled, and the
solvent removed under vacuum to yield a brown viscous
oil as a residue. This was
distilled at 105-120 °C at 0.2 mm/
Hg to
yield 8.8 g of
3,4-dimethoxy-5-hydroxybenzaldehyde as a
distillate
that set to white
crystals. Recrystallization from
toluene/hexane
gave a sample with the mp 64-65 °C. The literature mps are several,
ranging from at about 60 °C to about 70 °C.
A
solution of 4.7 g of
3,4-dimethoxy-5-hydroxybenzaldehyde in 75 mL
acetone was treated with 6.0 g powdered KI, 16 mL (21 g)
propyl
bromide, and 7.0 g finely powdered
anhydrous K2CO3, and this mixture
was held at reflux on a steam bath for 15 h. The reaction mixture was
added to 1 L H2O, made strongly basic, and extracted with 3x100 mL
CH2Cl2. The extracts were pooled, washed with 5%
NaOH, and the
solvent removed under vacuum yielding 8.8 g of a yellow oil,
undoubtedly containing
propyl iodide. This residue was
distilled at
133-145 °C at 0.15 mm/
Hg to yield 4.5 g of
3,4-dimethoxy-5-(n)-propoxybenzaldehyde as a white oil which did not
crystallize. There was an appreciable pot residue. This product was
clearly impure, having a minor, slower moving component not the
starting
phenol, as seen by TLC (on
silica gel, with
CH2Cl2 as a
developing
solvent). Fusion of a small amount of impure
aldehyde with
p-
anisidine produced a
crystalline anil which, on hydrolysis with
dilute acid, produced an
aldehyde sample free of this impurity. But
as this sample also remained as an oil, the above crude product was
used in the following preparation.
To a
solution of 3.8 g
3,4-dimethoxy-5-(n)-propoxybenzaldehyde in 50
mL
nitromethane, there was added 0.5 g
anhydrous ammonium acetate.
This was held at reflux for 50 min. The excess
nitromethane was
removed under vacuum and 2 volumes of boiling MeOH were added to the
residue. The hot
solution was decanted from some
residual in
solubles,
and on cooling spontaneously
crystallized. These solids were removed
by filtration, washed sparingly with MeOH and air dried yielding 3.3 g
yellow
crystals of
3,4-dimethoxy-beta-nitro-5-(n)-propoxynitrostyrene as
yellow
crystals melting at 79-81 °C. Recrystallization from MeOH or
cyclohexane neither improved the mp nor freed the product from a
residual opalescenceseen in the melt. Anal. (
C13H17NO5) C,H.
A
solution of 1.5 g LAH in 30 mL
anhydrous THF under He was cooled to
0 °C and vigorously stirred. There was added, dropwise, 1.0 mL of
100% H2SO4, followed by the dropwise addition of a
solution of 2.3 g
3,4-dimethoxy-beta-nitro-5-(n)-propoxynitrostyrene in 10 mL
anhydrous
THF, over the course of 5 min. The mixture was stirred at 0 °C for a
while, and then brought to a reflux on the steam bath. After cooling
again, the excess
hydride was destroyed with IPA added dropwise,
followed by the addition of about 10 mL of 10%
NaOH which was
sufficient to covert the solids to a white, granular form. These were
removed by filtration, the filter cake washed with IPA, the mother
liquor and filtrates were combined, and the
solvents were removed
under vacuum to yield an amber oil. This residue was added to 75 mL
dilute H2SO4 which produced a gummy in
soluble phase which was
physically removed with a spatula. The aqueous
phase was washed with
3x50 mL
CH2Cl2. It was then made basic with 25%
NaOH, and extracted
with 2x75 mL
CH2Cl2. The
solvent was removed from these pooled
extracts and the residue
distilled at 106-116 °C at 0.2 mm/
Hg to
provide 1.3 g of the product as a colorless liquid. This was
dissolved in 4 mL IPA, neutralized with about 20 drops of concentrated
HCl, and diluted with 4 volumes of
anhydrous Et2O added slowly with
continuous stirring. A white
crystalline salt
crystallized out
spontaneously and was isolated by filtration, washed first with IPA,
then with
Et2O, and air dried giving 1.3 g
3,4-dimethoxy-5-(n)-propoxyphenethylamine hydrochloride (MP) with a mp
of 170-171 °C. Anal. (
C13H22ClNO3) C,H.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 160 mg) There might have been some
disturbance at the three to four hour point, but it was extremely
light if at all.
(with 240 mg) No effects whatsoever.
EXTENSIONS AND EXTRAPOLATIONS: The loss of activity on lengthening the
carbon chain on the meta-oxygen from two to three (from
metaescaline
to
metaproscaline) discouraged any further exploration at this
specific point of the molecule. The
isopropyl analog
(
3,4-dimethoxy-5-(i)-propoxyphenethylamine,
metaisoproscaline, MIP)
was started and carried along as far as the
aldehyde, and abandoned
with the discovery that
metaproscaline was without activity. There
were other fish to fry.
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