J. R. Rodriguez et al. / Tetrahedron Letters 47 (2006) 5661–5663
5663
OBn
OBn
H
H
N
N
Bn2N
Bn2N
BnOH (1.1 eq.)
F
F
NaH (1.1 eq.), NMP
O
O
O
O
100 °C, 2 h
94%
130 g
F
OBn
Scheme 1. Application of the SNAr to bulk quantities.
130 g scale.11 The substitution compound was obtained
cleanly in a 94% isolated yield (Scheme 1).
4. Loupy, A.; Phillippon, N.; Pigeon, P.; Sansoulet, J. Synth.
Commun. 1990, 20, 2855–2864.
5. Balas, L.; Jhurry, D.; Latxague, L.; Grelier, S.; Morel, Y.;
Hamdani, M.; Ardoin, N.; Astruc, D. Bull. Soc. Chim. Fr.
1990, 127, 401.
In summary, we show the broad scope of the nucleo-
philic substitution of aromatic fluorine by primary and
secondary alkoxides in NMP, a simple and high yielding
reaction suitable for bulk scale.
6. Chaouchi, M.; Loupy, A.; Marque, S.; Petit, A. Eur. J.
Org. Chem. 2002, 67, 1278–1283.
7. DMF and NMP proved to be suitable solvents for this
reaction but NMP is more convenient for big scale
reactions for safety reasons associated with the use of
DMF with NaH: (a) Buckley, J.; Webb, R. L.; Laird, T.;
Ward, J. Chem. Eng. News 1982, 60, 5; (b) De Wall, G.
Chem. Eng. News 1982, 60, 43.
8. An improved method for the nucleophilic substitution of
fluorobenzene by alcohols for the synthesis of resorcinols
or catechols was published during the preparation of this
manuscript: Kim, A.; Powers, J. D.; Toczko, J. F. J. Org.
Chem. 2006, 71, 2170–2172.
9. The structures of the ortho, meta and para fluoroanisoles
were built in Maestro (v. 7.5.106, Schrodinger, Portland,
OR) in conformations known to be possible energy
minima. Each structure was subjected to full energy
minimization using Jaguar (HF/6-311G**, with accurate
SCF criteria and calculation of ESP-fit charges con-
strained by total charge and dipole moment. MO surfaces
were also requested for orbitals between HOMO À 1 and
LUMO + 1. Examination of the charges suggests that the
explanation for the lower reactivity of the para-fluoro
species is probably not electrostatic: the electrophilic
carbon had a partial charge of 0.32, 0.54 and 0.48 in the
ortho, meta and para isomers, respectively. On this basis,
the ortho should have been the least reactive. A further
possibility is that the para species is less reactive toward
nucleophiles for the displacement of fluorine due to a
lower orbital coefficient on the carbon atom to which the
fluorine is attached in this molecule. The LUMO plots
support this idea: the coefficient is near zero for both
forms of the para-fluoroanisole studied, but is nonzero for
both the other species in all conformations examined.
10. For the SNAr of aromatic fluorides by hindered alkoxides
see: Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org.
Chem. 1998, 63, 9594–9596.
Experimental: A 1 M solution of sodium benzyloxide in
N-methylpyrrolidone was prepared by adding benzyl
alcohol (1 equiv) to a suspension of NaH (1 equiv) in
NMP and stirring the mixture for 10 min. This freshly
prepared solution (2 equiv) was added to a 0.2 M solu-
tion of the fluorobenzene (1 equiv) in NMP. The reac-
tion was heated at 100 °C and was monitored by
LCMS until complete consumption of the starting mate-
rial. Water and ethyl acetate were added, the aqueous
layer was separated and the organic layer was washed
with water, dried over MgSO4, filtered and concen-
trated. The residue was chromatographed eluting with
hexane/EtOAc mixtures.
Acknowledgements
We thank Dr. Howard Broughton for his helpful discus-
sion on the reactivity of anisoles.
References and notes
1. Smith, M. B.; March, J. Advanced Organic Chemistry
Reactions, Mechanisms and Structure, 5th ed.; John Wiley
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