Luzzio and Chen
JOCNote
SCHEME 1. Preparation of Substituted Benzylic Nitroresorci-
nolic Ethers and Their Rearrangement to o-Arylmethyl Phenols
rearrangements of a variety of substrates using simple
organic Brønsted acids in halogenated aromatic solvents
without the use of high temperatures. Thus, so far, we have
prepared a number of polysubstituted biarylmethanes 1a-f
(Table 1) in modest to fair yield which would prove difficult
to prepare using Friedel-Crafts, o-metalation, or transition-
metal coupling chemistries. Our scheme starts with the
selection of the phenolic (nonmigrating) ring which possesses
ortho-positioned N,O-substituents. One ortho oxygen bears
the migrating benzyl group, while an additional ortho oxygen
is protected for additional elaboration at a later stage. It was
our intent that the benzylic ether oxygen which becomes the
phenol group through benzyl migration and its ortho nitro
group would later form a heterocycle. Hence, N,O hetero-
cycle formation is possible through reduction of the nitro
group to an amine followed by treatment with the requisite
coreactants to form a 2-substituted aryl or aminobenzox-
azole (vide supra).
The preparation of the benzylic ether rearrangement sub-
strates 2a-f (Table 1) was facilitated through our recently
reported procedure for the protection of phenolic ethers with
benzyl groups using ultrasound.9a 2-Nitroresorcinol mono-
methyl or monobenzyl ether was benzylated with a variety of
substituted arylmethyl chlorides using N,N-dimethylforma-
mide, potassium carbonate, and ultrasound, thereby afford-
ing the phenolic ether substrates 2a-f. Our initial
rearrangement experiments involved the selection of a sui-
table acid promotor for the conversion of substrate 2a to
nitrophenol 1a (Table 1). First, we determined that the Lewis
acids previously used in these rearrangements would be
unsuitable since dealkylation would occur when applied to
substrates bearing multiple alkylated phenolic hydroxyls.
Hence, we opted to examine simple Brønsted acids which
are inexpensive and easier to obtain commercially in high
purity. In contrast to results with aluminum chloride or
phosphotungstic acid,3d control reactions of benzyl phenyl
ether and trifluoroacetic acid or camphorsulfonic acid (CSA)
in fluoro- or chlorobenzene gave no rearrangement and
quantitative recovery of starting material. The employment
of trifluoroacetic acid (TFA) did promote the rearrangement
of 2a but with low yield of the nitrophenolic product 1a due
to competing cleavage to 4-methoxybenzyl alcohol.9b,c TFA
was tested on 2a in a range of solvents such as dichloro-
methane, nitromethane, fluorobenzene, chlorobenzene, ben-
zene, toluene, and 1,4-dichlorobenzene but was considered
too reactive. Fluorobenzene and chlorobenzene afforded the
best results in terms of reducing the unwanted side reactions
and maintaining a desirable reaction temperature. The opti-
mal yield of the methyl ether 2a was achieved with CSA
which is near the lower end of the Hammett acidity (H0)
range for nonfluorinated sulfonic acids (H0 = -1.0)13 as
opposed to TFA (H0 = -3.03).14
substitution pattern. While the “aroyl” Fries rearrangement
has been proven to accommodate up to three substituents on
the migrating ring, the substituents on the nonmigrating
phenolic ring have been limited to one. Furthermore, when
a diarylmethane rather than a diaryl ketone is the desired
product, the o-benzyl rearrangement would surpass the
analogous Fries transformation since the required one- or
two-step carbonyl f methylene conversion is now bypassed.
Our interest in the rearrangement reaction originally
stemmed from studies in which ortho rearrangement pro-
ducts formed to an appreciable extent during the preparation
of PMB ethers of ring-activated phenols.9 During a separate
study, the formation of an ortho-selective carbon-carbon
bond was of interest to us in preparing intermediates to
2-substituted 7-arylmethylbenzoxazoles and 2-substituted
7-aminobenzoxazoles (eq 3),10-12 thereby making such a
rearrangement worthy of study and optimization.
Accordingly, our initial experiments focused on rearran-
gements of the benzylaryl ether framework having electron-
releasing substituents on the migrating ring and both elec-
tron-releasing (alkoxy) and electron-withdrawing (nitro)
substituents on the phenolic ring (Scheme 1). In contrast to
previous studies which utilized mainly Lewis acid-promoted
rearrangement of benzylphenyl ether itself, we examined
(9) (a) Luzzio, F. A.; Chen, J J. Org. Chem. 2008, 73, 5621–5624. (b) For
earlier observations on side reactions involving TFA and other acid-
mediated debenzylation of phenolic benzyl ethers, see: Marsh, J. P.Jr.;
Goodman, L. J. Org. Chem. 1965, 30, 2491–2492. (c) Li, Z.; Cheng, B.; Su,
K.; Wang, F.; Yu, L Catal. Commun. 2009, 10, 518–521.
(10) For recent reports on the preparation of 2-arylbenzoxazoles as lead
pharmacophores, see: Harikrishnan, L. S.; Kamau, M. G.; Herpin, T. F.;
Morton, G. C.; Liu, Y.; Cooper, C. B.; Salvati, M. E.; Qiao, J. X.; Wang, T.
C.; Adam, L. P.; Taylor, T. S.; Chen, A. Y. A.; Yin, X.; Seethyala, R.;
Peterson, T. L.; Nirschl, D. S.; Miller, A. V.; Weigelt, C. A.; Appiah, K. K.;
O’Connell, J. C.; Lawrence, R. M. Bioorg. Med. Chem. Lett. 2008, 18, 2640–
2644. Wang, Y.; Sarris, K.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett.
2006, 47, 4823–4826.
(11) For recent reports on the preparation of 2-aminobenzoxazoles as
lead pharmacophores, see: Potashman, M. H.; Bready, J.; Coxon, A.;
DeMelfi, T. M.; DiPietro, L.; Doerr, N.; Elbaum, D.; Estrada, J.; Gallant,
P.; Germain, Gu, Y.; Harmange, J.-C.; Kaufman, S. A.; Kendall, R.; Kim, J.
L.; Kumar, G. N.; Long, A. M.; Neervannan, S.; Patel, V. F.; Polverino, A.;
Rose, P.; van der Plas, S.; Whittington, D.; Zanon, R.; Zhao, H. J. Med.
Chem. 2007, 50, 4351–4373. Lai, C.; Gum, R. J.; Daly, M.; Fry, E. H.;
Hutchins, C.; Abad-Zapatero, C.; von Geldern, T. W. Bioorg. Med. Chem.
Lett. 2006, 16, 1807–1810.
The intramolecularity of the rearrangement has been
previously investigated in the case of the isotopically labeled
parent benzyl phenyl ether substrate.15 With Lewis acid
(13) (a) Gazeau-Bureau, S.; Delcroix, D.; Martin-Vaca, B.; Bourissou,
D.; Navarro, C.; Magnet, S. Macromolecules 2008, 41, 3782–3784. (b) See
also: Olah, G. A.; Mathew, T.; Marinez, E. R.; Esteves, P. M.; Etzkorn, M.;
Razul, G.; Prakash, G. K. S. J. Am. Chem. Soc. 2001, 123, 11556–11561.
(14) Chambers, R. D. Fluorine in Organic Chemistry, 2nd ed.; CRC Press,
Blackwell: Oxford, U.K., 2004; p 93.
(12) Luzzio, F. A.; Wlodarczyk, M. T. Tetrahedron Lett. 2009, 50, 580–
583.
(15) Hart, L. S.; Waddington, C. R. J. Chem. Soc., Perkin Trans. 2 1985,
1607–1612.
5630 J. Org. Chem. Vol. 74, No. 15, 2009