Both DMF and NMP proved superior to either THF or
DMSO, with the former giving a slightly better yield. The lower
yield in THF is most likely due to the low boiling point of this
solvent, whereas the acidity of DMSO may play an unexpected
role leading to low conversions.
In view of the results shown above, the NaOt-Bu/DMF
combination was tried on a number of aromatic methyl ethers.
The results are summarized in Table 3. This methodology works
well in the presence of a broad variety of functional groups.
Electron-withdrawing groups on the ring clearly facilitate the
transformation and usually led to shorter reaction times, as has
been previously reported.8
Thus, cyano (entries 1, 3, and 4), aldehyde (entry 11), and
nitro (entry 18) groups gave very fast conversions, while the
presence of less electronegative groups such as keto (entries
12 and 13), imidazolyl (entry 16), or dimethoxy (entry 19)
required longer reaction times.
The substitution pattern on the ring plays an important role
on the outcome of the reaction and, when both ortho and para
positions relative to the electron-withdrawing group are available
for deprotection, the former undergoes the transformation
preferentially (entry 3). On the other hand, when both meta and
para positions compete, the latter reacts exclusively (entry 4),
which agrees with what is expected on the basis of the
electronics of the ring. When several methoxy groups are present
on the ring in equivalent positions, the amount of thiol can be
controlled to selectively accomplish mono- or bisdeprotection,
as is shown in entries 2, 14, and 19. This selectivity is further
enhanced by the fact that once the first deprotection has taken
place, the ring becomes more electron-rich and additional
demethylation is disfavored. It is worth highlighting that
compounds with relatively acidic protons can be deprotected
under these conditions in fair to excellent yields, such as the
ketones in entries 12 and 15. When the ester group is present
(entries 5, 6, and 7), low to fair yields are obtained. The yield
for entry 6, where meta-substitution is present, was especially
low, even after attempts to optimize the reaction conditions.
As a side reaction, the formation of the byproduct from the
attack of the thiolate species on the carbonyl group to give the
corresponding thioester was observed. Several substrates with
the carboxylic acid functionality were also tested, but no reaction
was observed due to the precipitation of their sodium or lithium
salts, when LiOt-Bu was used as base, in the reaction medium.
The major limitation for this methodology has to do with
the absence of electron-withdrawing groups on the ring; thus,
2-methoxynaphthalene gave incomplete reaction even after
prolonged reaction times (up to 7 h at reflux) and a large excess
of thiol (up to 4 equiv). Also, compounds with triple bonds
([(3-methoxyphenyl)ethynyl]trimethylsilane), with very acidic
hydrogens (p-anisamide), or more heavily functionalized (4-
chloro-3-nitroanisole) gave decomposition. 4-Fluoroanisole also
gave partial decomposition together with some product resulting
from the nucleophilic aromatic substitution of the fluorine atom
by the thiol, while 4-methoxychalcone gave a complex mixture
of products where the known fact that thiols can give rise to
radical processes may have played a significant role.9
In conclusion, a useful demethylation protocol for aromatic
methyl ethers has been developed that is compatible with an
extensive range of functional groups on the aromatic ring and
that circumvents the smell problems associated with the use of
ethanethiol. This methodology can be useful to both discovery
and process chemists as a practical way to have access to
phenols.
Experimental Section
The following experimental procedure to prepare 4-hydroxy-1-
naphthonitrile (entry 1) is representative: An oven-dried, 50-mL,
round-bottomed flask equipped with a magnetic stirrer and under
a nitrogen atmosphere was charged with 2-(diethylamino)ethanethiol
HCl (1.28 g, 7.5 mmol). N,N-dimethylformamide (10 mL) was
added via syringe, and the flask was cooled in an ice water bath.
When the internal temperature was below 5 °C, solid NaOt-Bu (1.54
g, 16.1 mmol) was added in one portion After 5 min, the cooling
bath was removed, and the white suspension was allowed to warm
to ambient temperature. After 15 min, 4-methoxy-1-naphthonitrile
was added in one portion, and the contents of the flask were heated
to reflux for 30 min. TLC analysis (hexanes/ethyl acetate 1/1 as
mobile phase) and mass spectrometry analyses showed complete
reaction. The mixture was allowed to cool to ambient temperature,
and the flask was placed in an ice water bath. To the flask was
added 1 N HCl dropwise to bring the pH to 1 followed by the
addition of water (25 mL). The aqueous phase was extracted with
ethyl acetate (3 × 25 mL), and the combined organic extracts were
washed with water (3 × 10 mL) and saturated brine (10 mL) and
dried over MgSO4. The solvent was removed under vacuum to give
a brown solid that was chromatographed (hexanes/ethyl acetate 1/1
as mobile phase) to give 0.77 g (91%) of 4-hydroxy-1-naphthonitrile
as a white solid: mp 176-180 °C. IR: 3350, 3104, 2229, 2217,
1
1577, 1520, 1384, 1353, 1221, 821, 754 cm-1. H NMR (CDCl3,
400 MHz): δ 11.46 (s, 1 H), 8.22-8.24 (d, 1 H, J ) 7.99 Hz),
7.92-7.97 (m, 2 H), 7.70-7.74 (ddd, 1 H, J ) 8.33, 6.97, 1.27
Hz), 7.56-7.61 (ddd, 1 H, J ) 8.29, 6.92, 1.17 Hz), 6.94-6.96 (d,
1 H, J ) 8.19 Hz). MS m/z ) 168 (M - H)+. Anal. Calcd for
C11H7NO: C, 78.09; H, 4.17; N, 8.28. Found: C, 77.83; H, 4.28;
N, 8.23.
Acknowledgment. The authors would like to thank Drs.
Daniel T. Belmont and D. Keith Anderson from the Research
API group at Pfizer Global R&D for reviewing this manuscript.
Supporting Information Available: Synthetic procedure and
complete characterization data for entries 2 through 19 in Table 1.
This material is available free of charge via the Internet at
JO0611059
(8) (a) Dodge, J. A.; Stocksdale, M. G.; Fahey, K. J.; Jones, C. D. J.
Org. Chem. 1995, 60, 739-741. Hansson, C.; Wickberg, B. Synthesis 1976,
191-192.
(9) Meissner, J. W. G.; van der Lann, A. C.; Pandit, U. K. Tetrahedron
Lett. 1994, 35, 2757-2760.
J. Org. Chem, Vol. 71, No. 18, 2006 7105