(entries 7–9). Such behaviour was observed also in the case
of tricyclic 2,3-naphthalimide (entry 10), which reacted with
(R)-epichlorohydrin under our optimized conditions, affording
uniquely the haloalcohol 9 in excellent regio- and enantioselec-
tive fashion.
After confirming that our potassium fluoride supported
on alumina-promoted conditions were indeed adequate for
promoting N-alkylations, we then decided to augment our
synthetic efforts towards checking the chemoselectivity of the
alkylation reaction, by applying our experimental conditions to
3-aminophtalimide 10, bearing two potential nucleophilic sites:
the NH of the cyclic imide and the arylamino functionality.
In fact, the limitation typically found in the N-alkylations of
structures bearing more than one nitrogen atom is the necessity
of using vulnerable nitrogen protecting groups, because of the
virtually impossible selective functionalization of these naked
groups.27 Results are pictured in Scheme 1.
moted by KF-Alumina in the more environmentally friendly
green solvent 2-methyltetrahydrofuran (MeTHF). This method
offers a series of advantages over classical procedures, including
high regio- and enantioselective pathways in the presence
of asymmetric bifunctional structures, wide applicability to
different electrophiles as well as substituted phthalimide nucleus,
and expands the range of organic procedures which can be
conducted in MeTHF.
Acknowledgements
The authors thank Pen A Kem, LLC (Memphis, Tennessee
(USA) for kindly providing us 2-methyltetrahydrofuran. One
of the authors (V. Pace) gratefully acknowledges the Spanish
Ministry of Science and Innovation for a PhD fellowship (Ref.
AP2005-5112).
Notes and references
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Scheme 1
Remarkably, by using only one equivalent of allylating agent
in MeTHF/KF–Al2O3, functionalization occurred exclusively
at the imidic nitrogen, affording exclusively compound 11, in
which the arylamino function remained untouched. (Scheme 1)
This experimental observation may be explained on the basis
of the higher acidity of the imidic proton (compared to the
aminic ones), which is preferentially removed in the presence of
a relatively strong base as KF-Alumina.
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the derived from the aryl amino moiety. Evidently, the milder
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appears to constitute a confirmation of the poor result observed
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In conclusion, we described a convenient and really valuable
method for the N-alkylation of phthalimide derivatives pro-
1382 | Green Chem., 2010, 12, 1380–1382
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