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HETEROCYCLES, Vol. 94, No. 7, 2017
Lastly, while keeping THF as the solvent, we increased the amount of the alcohol, PPh3 and DEAD to four
equivalents instead of two (entry 26). Although not necessarily significant, the amount of O-alkylated
product did increase, leading us to wonder what an even higher equivalent increase in reactants would do.
In the last reaction (entry 27), we increased to eight equivalents of the alcohol, PPh3 and DEAD. In this case,
only the O-alkylated product was observed. By swamping the reaction with available electrophile, the more
electronegative phenolic oxygen wins out. With an overabundance of electrophile, kinetics now determine
the reaction outcome.
In conclusion, we have demonstrated that the location of the ring nitrogen relative to the phenolic oxygen
can have a dramatic effect on O- versus N-alkylation. It tautomerism is not allowed or sterics block the
nitrogen atom, then only O-alkylation is allowed. Also, the solvation of the conjugate base, as well as the
reacting electrophile, can likewise have a large influence on the final ratio of O- versus N-alkylation in the
quinolinol and isoquinolinol ring systems, which until now have been unexplored. By varying the solvent,
reacting heterocycle and electrophilic alcohol, one should be able to shift the reaction toward whichever O-
or N-alkylated product is desired. With the Mitsunobu reaction’s mild conditions and tolerability of a large
variety of functional groups, when compared to other similar reactions such as the Williamson alkylation,12
which have harsher conditions and lower amount of allowable functional groups, the Mitsunobu reaction
continues to be widely used in many modern synthetic schemes due to its ease and versatility.
EXPERIMENTAL
PPh3 (89 mg, 0.34 mmole, 2 eq) and the quinolinol or isoquinolinol (25 mg, 0.17 mmole, 1 eq) were
combined in a glass vial and purged with nitrogen. THF (700 µL) was then added followed by benzyl
alcohol (44 µL, 0.34 mmole, 2 eq). A 40% by weight solution of DEAD in toluene (170 µL, 0.34 mmole, 1
o
eq) was then added dropwise to keep the reaction temperature below 30 C. The reaction mixture was
shaken at room temperature overnight and then purified on a Waters preparative LC/MS system with a
gradient of 0 to 60% MeCN-H2O to give the desired product with yields ranging from 50% to 98%. In
instances where the isomers were not able to be separated, the percentage ratio was determined by 1H NMR.
Purified products were characterized by 1H and 13C NMR.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Sanofi for their support and the resources necessary for the majority of
this work, as well as Dr. Zhongli Gao, Dr. John Hofferberth, Dr. David Hilmey and Dr. Joseph Kim in their
assistance with this manuscript.