A hierarchy of aryloxide deprotection by boron tribromide

Article abstract of DOI:10.1021/ol0489898

Aryl propargyl ethers and esters are cleaved selectively in the presence of aryl methyl ethers and esters by boron tribromide in dichloromethane. Under the same conditions, allyl ethers undergo very rapid Claisen rearrangement, and benzyl ethers are also cleaved more rapidly than propargyl. A mechanism involving intramolecular delivery of bromide to the propargyl terminus is proposed.

Full text of DOI:10.1021/ol0489898

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2777-2779
A Hierarchy of Aryloxide Deprotection
by Boron Tribromide
Sreenivas Punna, Ste´phane Meunier, and M. G. Finn*
Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
mgfinn@scripps.edu
Received June 1, 2004
ABSTRACT
Aryl propargyl ethers and esters are cleaved selectively in the presence of aryl methyl ethers and esters by boron tribromide in dichloromethane.
Under the same conditions, allyl ethers undergo very rapid Claisen rearrangement, and benzyl ethers are also cleaved more rapidly than
propargyl. A mechanism involving intramolecular delivery of bromide to the propargyl terminus is proposed.
Cleavage of aryl ethers and esters by Lewis acids constitutes
a common strategy for the unmasking of the ArOH and
ArCO2H functional groups.1 The methoxy unit, being stable
to a vast array of reaction conditions, is particularly well
utilized, although its deprotection with strong Lewis acids
is not compatible with some functional groups. In contrast,
the propargyloxy unit is rarely used in total synthesis,
probably because of the lack of a convenient and selective
deprotective protocol. The known methods include (1)
palladium-catalyzed reactions, which usually proceed at
elevated temperature in moderate to high yields;2 (2) the use
of low-valent titanium species, incompatible with subtrates
presenting easily reduced functional groups such as nitro or
carbonyl;3 (3) nickel-catalyzed electroreductions;4 (4) cleav-
age using a tetrathiomolybdate reagent, which has to be
prepared in a first step;5 and (5) a two-step protocol involving
the isomerization of prop-2-ynyl ethers to the corresponding
allenyl ethers, followed by cleavage under neutral and acidic
conditions.6 We report here an easy and efficient method
for the selective deprotection of aryl propargyl ethers or
esters. Most significantly, the protocol allows for selectivity
among aryl benzyl, propargyl, and methyl protecting groups.
Table 1 summarizes the results. In independent reactions,
propargyl 1-naphthyl ether was cleaved to 1-naphthol within
5 min at room temperature, whereas the methyl ether required
30 min (entries 1 and 2). When both functional groups were
present on the same molecule, the propargyl ether was
cleaved selectively by 1 equiv of BBr3 at room temperature
or -20 °C (entries 3 and 4). Depropargylation also occurred
smoothly in the presence of bromide and nitro substituents
(entries 5 and 6), but more time was required for the electron-
deficient substrate. Similarly, propargyloxy cleavage was
faster in the presence of p-methoxy substitution compared
to m-methoxy or -carbomethoxy (entry 3 vs 4 and 7). The
acid-sensitive tetrahydropyranyl group was not tolerated
(entry 8). Allylic ethers underwent rapid BBr3-mediated
Claisen rearrangement,7 leaving methyl and propargyl ethers
untouched (entries 9 and 10). Similarly, a benzyl ether
reacted more rapidly than propargyl (entry 11).8
Propargyl esters were cleaved to the carboxylic acids in
the presence of methyl ether and methyl ester groups (entries
12 and 13). Propargylic amides, however, were resistant to
(1) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999. (b) Schelhaas,
M.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 2056-2083.
(2) (a) Pal, M.; Parasuraman, K.; Yeleswarapu, K. R. Org. Lett. 2003,
5, 349-352. (b) Zhang, H. X.; Guibe´, F.; Balavoine, G. Tetrahedron Lett.
1988, 29, 619-622.
(3) Nayak, S. K.; Kadam, S. M.; Banerji, A. Synlett 1993, 581-582.
(4) Oliviero, S.; Dun˜ach, E. Tetrahedron Lett. 1997, 38, 6193-6196.
(5) (a) Swamy, V. M.; Ilankumaran, P.; Chandrasekaran, S. Synlett 1997,
513-514. (b) Prabbu, K. R.; Devan, N.; Chandrasekaran, S. Synlett 2002,
1752-1778.
(6) Mereyala, H. B.; Gurrala, S. R.; Mohan, S. K. Tetrahedron 1999,
55, 11331-11342.
(7) (a) Cairns, N.; Harwood, L. M.; Astles, D. P.; Orr, A. J. Chem. Soc.,
Chem. Commun. 1986, 182-183. (b) Cairns, N.; Harwood, L. M.; Astles,
D. P.; Orr, A. J. Chem. Soc., Perkin Trans. 1 1994, 3095-3100.
(8) Paliakov, E.; Strekowski, L. Tetrahedron Lett. 2004, 45, 4093-4095.
10.1021/ol0489898 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/09/2004

Table 1. Treatment of Ethers and Esters with BBr3
a Unless otherwise indicated, all reactions were performed with 1 equiv of BBr3 (1 M in CH2Cl2) and monitored by TLC. Each was quenched by the
addition of water; the products were extracted with CH2Cl2 or ethyl acetate and purified by flash chromatography. b Isolated yields of pure compounds after
chromatography.
cleavage. Thus, both secondary and tertiary propargyl amides
bearing methyl ether groups were recovered intact after
extended treatment at room temperature with 1 equiv of BBr3.
The corresponding methyl-cleaved phenols were obtained
in modest yield (but as the major component of mixtures)
with only the use of excess reagent (entries 14 and 15). These
observations suggest that amides bind to the boron center
and passivate the Lewis acid. The more complex structure
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Org. Lett., Vol. 6, No. 16, 2004

shown in entry 16 gave further evidence of this hypothesis,
being cleanly mono-depropargylated when treated with 2
equiv of BBr3. This result also shows that propargyl ethers
can be cleaved in preference to methyl esters. A preliminary
test demonstrated that an aliphatic propargyl ether was also
deprotected by BBr3, albeit in lower yield (entry 17).
A suggested reaction mechanism for depropargylation is
shown in Scheme 1. Activation of the propargyl group by
2,6-dimethyl-1,4-dipropargyl ether shown in entry 19: while
a small amount of the doubly deprotected hydroquinone was
isolated, none of the 4-propargyloxy-1-phenol was observed.
2,6-Dimethyl substitution was not sufficient to overcome the
more reactive nature of the propargyl ether in entry 20, but
tert-butyl groups served to direct BBr3 to the unguarded
4-methoxy position in entry 21.
These studies establish the order of reactivity for depro-
tection by BBr3 depicted in Scheme 1. Benzyl, propargyl,
and methyl ethers can thereby be deprotected sequentially
using stoichiometric amounts of boron tribromide, adding
an additional level of selectivity to protecting group opera-
tions for the phenolic unit.
Scheme 1
Acknowledgment. We thank the NIH (R01-ED000432-
02) and the Skaggs Institute for Chemical Biology for support
of this work.
Supporting Information Available: Experimental pro-
cedures and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
coordination of the Lewis acid is proposed to lead to intra-
or intermolecular delivery of bromide to give bromoallene
by concomitant C-O bond cleavage.9 Consistent with this
hypothesis was the observed failure of a methylated (2-
butynyl) derivative to undergo clean deprotection (entry 18),
presumably because bromide addition is hindered. The
importance of the precoordination step is supported by three
observations. (a) The reaction does not occur in donor
solvents (THF, diethyl ether). (b) It is slowed by electron-
withdrawing substituents (see above). (c) Steric hindrance
ortho to the propargyl ether moiety inhibits the process. Thus,
substantial selectivity was observed for the 4-position of the
OL0489898
(9) Deuterium NMR monitoring of the reaction of ArOCH2CCD (Ar )
1-naphthyl) with BBr3 showed the formation of a signal in the aliphatic
region (4.2 ppm) and several vinylic resonances (6-8 ppm), but none
corresponding to the intact propargyl unit (see the Supporting Information).
This suggests that the alkyne unit participates in propargyl ether cleavage,
as opposed to simple rupture or displacement of the O-CH2 bond. The
data also suggest the presence of benzofuran and related compounds as
minor byproducts derived from propargylic Claisen rearrangement: (a) Box,
V. G. S.; Meleties, P. C. Heterocycles 1998, 48, 2173-2183. (b) Cruz-
Almanza, R.; Perez-Florez, F.; Brena, L.; Tapia, E.; Ojeda, R.; Fuentes, A.
J. Heterocycl. Chem. 1995, 32, 219-222. (c) Otter, B. A.; Saluja, S. S.;
Fox, J. J. J. Org. Chem. 1972, 37, 2858-2864.
Org. Lett., Vol. 6, No. 16, 2004
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