SYNTHESIS: To a solution of 49.2 g 5,6,7,8-tetrahydronaphthol
(5-hydroxytetralin) in 100 mL MeOH, there was added 56 g methyl iodide
followed by a solution of 24.8 g KOH pellets (85% purity) in 100 mL
boiling MeOH. The mixture was heated in a 55 °C bath for 3 h (the
first white solids of potassium iodide appeared in about 10 min). The
solvent was stripped under vacuum, and the residues dissolved in 2 L
H2O. This was acidified with HCl, and extracted with 4x75 mL CH2Cl2.
After washing the organic phase with 3x75 mL 5% NaOH, the solvent was
removed under vacuum to give 48.2 g of a black residue. This was
distilled at 80-100 °C at 0.25 mm/Hg to provide 33.9 g
5-methoxy-1,2,3,4-tetrahydronaphthalene as a white oil. The NaOH
washes, upon acidification and extraction with CH2Cl2 gave, after
removal of the solvent under vacuum and distillation of the residue at
0.35 mm/Hg, 11.4 g of recovered starting phenol.
A mixture of 61.7 g POCl3 and 54.3 g N-methylformanilide was heated on
the steam bath for 15 min which produced a deep red color. This was
added to 54.3 g of 5-methoxy-1,2,3,4-tetrahydronaphthalene, and the
mixture was heated on the steam bath for 2 h. The reaction mixture
was quenched in 1.2 L H2O with very good stirring. The oils generated
quickly turned to brown granular solids, which were removed by
filtration. The 79 g of wet product was finely triturated under an
equal weight of MeOH, filtered, washed with 20 mL ice-cold MeOH, and
air dried to yield 32.0 g of
4-methoxy-5,6,7,8-tetrahydronaphthaldehyde as an ivory-colored solid.
The filtrate, on standing, deposited another 4.5 g of product which
was added to the above first crop. An analytical sample was obtained
by recrystallization from EtOH, and had a mp of 57-58 °C. Anal.
(C12H14O2) C,H.
To a solution of 25.1 g 4-methoxy-5,6,7,8-tetrahydronaphthaldehyde in
300 mL CH2Cl2 there was added 25 g 85% m-chloroperoxybenzoic acid at a
rate that was commensurate with the exothermic reaction. Solids were
apparent within a few min. The stirred reaction mixture was heated at
reflux for 8 h. After cooling to room temperature, the solids were
removed by filtration and washed lightly with CH2Cl2. The pooled
filtrate and washes were stripped of solvent under vacuum and the
residue dissolved in 100 mL MeOH and treated with 40 mL 25% NaOH.
This was heated on the steam bath for an hour, added to 1 L H2O, and
acidified with HCl, producing a heavy crystalline mass. This was
removed by filtration, air dried, and distilled at up to 170 °C at 0.2
mm/Hg. There was thus obtained 21.4 g of
4-methoxy-5,6,7,8-tetrahydronaphthol as an off-white solid with a mp
of 107-114 °C. An analytical sample was obtained by recrystallization
from 70% EtOH, and melted at 119-120 °C. Hexane is also an excellent
recrystallization solvent. Anal. (C11H14O2) C,H. As an alternate
method, the oxidation of the naphthaldehyde to the naphthol can be
achieved through heating the aldehyde in acetic acid solution
containing hydrogen peroxide. The yields using this route are
consistently less than 40% of theory.
A solution of 21.0 g of 4-methoxy-5,6,7,8-tetrahydronaphthol in 100 mL
acetone in a 1 L round-bottomed flask, was treated with 25 g finely
ground anhydrous K2CO3 and 26 g methyl iodide. The mixture was held
at reflux on the steam bath for 2 h, cooled, and quenched in 1 L H2O.
Trial extraction evaluations have shown that the starting phenol, as
well as the product ether, are extractable into CH2Cl2 from aqueous
base. The aqueous reaction mixture was extracted with 3x60 mL CH2Cl2,
the solvent removed under vacuum, and the residue (19.6 g) was
distilled at 90-130 °C at 0.3 mm/Hg to give 14.1 g of an oily white
solid mixture of starting material and product. This was finely
ground under an equal weight of hexane, and the residual crystalline
solids removed by filtration. These proved to be quite rich in the
desired ether. This was dissolved in a hexane/CH2Cl2 mixture (3:1 by
volume) and chromatographed on a silica gel preparative column, with
the eluent continuously monitored by TLC (with this solvent system,
the Rf of the ether product was 0.5, of the starting phenol 0.1). The
fractions containing the desired ether were pooled, the solvent
removed under vacuum and the residue, which weighed 3.86 g, was
dissolved in 1.0 mL hexane and cooled with dry ice. Glistening white
crystals were obtained by filtration at low temperature. The weight
of 5,8-dimethoxytetralin isolated was 2.40 g and the mp was 44-45 °C.
GCMS analysis showed it to be largely one product (m/s 192 parent peak
and major peak), but the underivitized starting phenol has abysmal GC
properties and TLC remains the best measure of chemical purity.
A well-stirred solution of 3.69 g 5,8-dimethoxytetralin in 35 mL
CH2Cl2 was placed in an inert atmosphere and cooled to 0 °C with an
external ice bath. There was then added, at a slow rate, 4.5 mL
anhydrous stannic chloride, which produced a transient color that
quickly faded to a residual yellow. There was then added 2.0 mL
dichloromethyl methyl ether, which caused immediate darkening. After
a few min stirring, the reaction mixture was allowed to come to room
temperature, and finally to a gentle reflux on the steam bath. The
evolution of HCl was continuous. The reaction was then poured into
200 mL H2O, the phases separated, and the aqueous phase extracted with
2x50 mL CH2Cl2. The organic phase and extracts were pooled, washed
with 3x50 mL 5% NaOH, and the solvent removed under vacuum. The
residue was distilled at 120-140 °C at 0.3 mm/Hg to give 3.19 g of a
white oil that spontaneously crystallized. The crude mp of
1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde was 70-72 °C. An
analytical sample from hexane had the mp 74-75 °C. The GCMS analysis
showed only a single material (m/s 220, 100%) with no apparent
starting dimethoxytetralin present. Attempts to synthesize this
aldehyde by the Vilsmeier procedure (POCl3 and N-methylformanilide)
gave complex mixtures of products. Synthetic efforts employing
butyllithium and DMF gave only recovered starting material.
To a solution of 1.5 g
1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde in 20 g nitromethane
there was added 0.14 g anhydrous ammonium acetate and the mixture
heated on the steam bath for 50 min. The rate of the reaction was
determined by TLC monitoring, on silica gel with CH2Cl2 as the moving
solvent; the Rf of the aldehyde was 0.70, and of the product
nitrostyrene, 0.95. Removal of the volatiles under vacuum gave a
residue that spontaneously crystallized. The fine yellow crystals
that were obtained were suspended in 1.0 mL of MeOH, filtered, and air
dried to yield 1.67 g
2,5-dimethoxy-beta-nitro-3,4-(tetramethylene)styrene with a mp of
151.5-152.5 °C. Anal. (C14H17NO4) C,H.
DOSAGE: unknown.
DURATION: unknown
EXTENSIONS AND COMMENTARY: The road getting to this final product
reminded me of the reasons why, during the first few billion years of
the universe following the big bang, there was only hydrogen and
helium. Nothing heavier. When everything had expanded enough to cool
things sufficiently for the first actual matter to form, all was
simply very energetic protons and neutrons. These were banging into
one-another, making deuterium nuclei, and some of these got banged up
even all the way to helium, but every time a helium nucleus collided
with a particle of mass one, to try for something with mass five, the
products simply couldn't exist. Both Lithium-5 and Helium-5 have the
impossible half-lives of 10 to the minus 21 seconds. Hence, in the
primordial soup, the only way to get into something heavier than
helium was to have a collision between a couple of the relatively
scarcer heavy nuclei, or to have a three body collision. Both of
these would be extremely rare events, statistically. And if a few got
through, there was another forbidden barrier at mass 8, since
Beryllium-8 has a half life of 10 to the minus 16 seconds. So
everything had to wait for a few suns to burn down so that they could
process enough helium into heavy atoms, to achieve some nuclear
chemistry that was not allowed in the early history of the universe.
And in the same way, there were two nearly insurmountable barriers
encountered in getting to 2C-G-4 and G-4. The simple act of
methylating an aromatic hydroxyl group provided mixtures that could
only be resolved into components by some pretty intricate maneuvers.
And when that product was indeed gotten, the conversion of it into a
simple aromatic aldehyde resisted the classic procedures completely,
either giving complex messes, or nothing. And even now, with these
two hurdles successfully passed, the presumed simple last step has not
yet been done. The product 2C-G-4 lies just one synthetic step (the
LAH reduction) away from completion, and the equally fascinating G-4
also that one last reduction step from being completed. Having gotten
through the worst of the swamp, let's get into the lab and finish up
this challenge. They will both be active compounds.
Back]
]