Solid-supported acids as mild and versatile reagents for the deprotection of aromatic ethers

Article abstract of DOI:10.1021/ol070781+

Equation Presented p-Toluene sulfonic acid (p-TsOH) immobilized either on polystyrene (PS) or silica (Si) was found to be effective in cleaving aromatic ethers containing isopropyl, tert-butyl, allyl, and benzyl groups, as well as mono-, di-, and trimethoxylated benzyl groups, in moderate to excellent yields (54-95%). These protecting groups could be selectively deprotected when they were simultaneously present on the same or different aromatic rings in a substrate.

Full text of DOI:10.1021/ol070781+

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2637-2640
Solid-Supported Acids as Mild and
Versatile Reagents for the Deprotection
of Aromatic Ethers
Poonsakdi Ploypradith,*,† Pannarin Cheryklin,‡ Nattisa Niyomtham,†
Daniel R. Bertoni,§ and Somsak Ruchirawat†,‡
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, VipaVadee-Rangsit
Highway, Bangkok, Thailand 10210, and Program on Research and DeVelopment of
Synthetic Drugs, Institute of Science and Technology for Research and DeVelopment,
Mahidol UniVersity, Salaya Campus, Nakhon Pathom, Thailand
poonsakdi@cri.or.th
Received April 1, 2007
ABSTRACT
p-Toluene sulfonic acid (p-TsOH) immobilized either on polystyrene (PS) or silica (Si) was found to be effective in cleaving aromatic ethers
containing isopropyl, tert-butyl, allyl, and benzyl groups, as well as mono-, di-, and trimethoxylated benzyl groups, in moderate to excellent
yields (54−95%). These protecting groups could be selectively deprotected when they were simultaneously present on the same or different
aromatic rings in a substrate.
Protecting groups are important tools in organic synthesis
as they have found extensive use in many different areas of
complex syntheses of natural products, biomolecules, and
materials.1 Crucial features of protecting groups are their ease
of preparation and removal as well as their relative stability
toward different reaction conditions. A number of moieties
such as benzyl, isopropyl, tert-butyl, and mono- or poly-
methoxylated benzyl, among others, have been developed
as protecting groups for both aliphatic and aromatic hydroxy
functionalities.2 Reaction conditions for preparing and re-
moving these protecting groups have been investigated.3 New
reagents and reaction conditions have been continually
developed for protecting and/or deprotecting purposes.4
Current awareness and interest in green chemistry has
prompted many research groups, including ours, to investi-
† Chulabhorn Research Institute.
(2) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999. (b) Kocienski,
P. J. Protecting Groups, 3rd ed.; Georg Thieme Verlag: Stuttgart, Germany,
2003.
‡ Mahidol University.
§ Present address: Department of Chemistry, University of Michigan,
Ann Arbor, MI 48109.
(1) (a) Hanessian, S.; Reddy, G. J.; Chahal, N. Org. Lett. 2006, 8, 5477-
5480. (b) Jones, S. B.; He, L.; Castle, S. L. Org. Lett. 2006, 8, 3757-
3760. (c) Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960-
15961. (d) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki,
M. J. Am. Chem. Soc. 2006, 128, 16989-16999.
(3) (a) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979,
2593-2598. (b) Cruz-Almanza, R.; Pe´rez-Flores, F. J.; Avila, M. Synth.
Commun. 1990, 20, 1125-1131. (c) Ma, S.; Venanzi, L. M. Tetrahedron
Lett. 1993, 34, 8071-8074. (d) Molna´r, A.; Beregsza´szi, T. Tetrahedron
Lett. 1996, 37, 8597-8600.
10.1021/ol070781+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/12/2007

gate other alternatives in performing reactions.5 The use of
solid supports, as either reagents or anchors, contributes
significantly to the progress of practicing green chemistry
because they render the reaction more efficient and envi-
ronmentally friendly. Employing solid-supported reagents,
in particular, generates less organic and aqueous waste as a
result of simplified experimental procedures. Herein, we wish
to report the results of our investigation of the generality
and selectivity in the use of p-TsOH immobilized on either
silica (PTS-Si) or polystyrene (PS)-divinyl benzene (DVB)
polymer (Amberlyst-15) for the deprotection of aromatic
ethers.
Table 1. Deprotection of Vanillin Ethers (1-7) to Vanillin
with Amberlyst-15 and PTS-Sia
Vanillin was chosen as a model and was converted into
the corresponding ethers by using either conventional or
newly reported procedures.6 A total of seven ethers (1-7)
were prepared in 30-97% yields. Table 1 summarizes the
result of our investigation. All ethers of vanillin were found
to be effectively cleaved in 54-95% yields under mild
reaction conditions, employing either Amberlyst-15 or PTS-
Si in toluene at elevated temperatures (e110 °C) with or
without methanol as additive in relatively short reaction times
(e4 h).
In most cases, only substoichiometric amounts of the acids
(0.3-0.6 equiv) were required. Different protecting groups
require slightly different reaction conditions for their removal.
Throughout the reactions, the pH of the reactions as measured
from toluene remained neutral. Decreasing the amount of
acids employed in the reactions resulted in longer reaction
time. In addition, the deprotection reactions employing PTS-
Si were generally faster than those employing Amberlyst-
15 under identical conditions due to the greater surface area
of silica.7
a Unless otherwise noted, all reactions were performed in toluene with
4 equiv of methanol. b Numbers represent the yields of vanillin ethers. c A
) Amberlyst-15; B ) PTS-Si. d The lowest amount of acids required. e The
lowest temperature required. f Isolated yield of vanillin. g Similar results
were obtained in the presence and absence of methanol. h Vanillin was
obtained in 98% yield under similar reaction conditions, using 1.1 equiv of
acid (see ref 5b). i At room temperature, the reaction required 6 d (144 h)
and provided vanillin in 91% yield. j Vanillin was obtained in 91% yield
when 1.1 equiv of the acid was employed at 110 °C for 18 h. k The reaction
proceeded to furnish vanillin in 93% yield at 65 °C for 3 h. l At 110 °C,
the reaction required only 0.25 h to complete, providing vanillin in 90%
yield.
(4) (a) Ballini, R.; Bigi, F.; Carloni, S.; Maggi, R.; Sartori, G. Tetrahedron
Lett. 1997, 38, 4169-4172. (b) Cappa, A.; Marcantoni, E.; Torregiani, E.
J. Org. Chem. 1999, 64, 5696-5699. (c) Monoharan, M.; Lu, Y.; Casper,
M. D.; Just, G. Org. Lett. 2000, 2, 243-246. (d) Papageorgiou, E. A.; Guant,
M. J.; Yu, J.-Q.; Spencer, J. B. Org. Lett. 2000, 2, 1049-1051. (e)
Marcantoni, E.; Massaccesi, M.; Torregiani, E. J. Org. Chem. 2001, 66,
4430-4432. (f) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Srividya, R.; Yadav,
J. S. Org. Lett. 2001, 3, 1149-1151. (g) Markovic´, D.; Vogel, P. Org.
Lett. 2004, 6, 2693-2696. (h) Ritter, T.; Stanek, K.; Larrosa, I.; Carreira,
E. M. Org. Lett. 2004, 6, 1513-1514. (i) Punna, S.; Meunier, S.; Finn, M.
G. Org. Lett. 2004, 6, 2777-2779. (j) Fujioka, H.; Sawama, Y.; Murata,
N.; Okitsu, T.; Kubo, O.; Matsuda, S.; Kita, Y. J. Am. Chem. Soc. 2004,
126, 11800-11801. (k) Fujioka, H.; Okitsu, T.; Sawama, Y.; Murata, N.;
Li, R.; Kita, Y. J. Am. Chem. Soc. 2006, 128, 5930-5938. (l) Bartoli, G.;
Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre, P.; Sambri, L. Org.
Lett. 2005, 7, 427-430. (m) Bartoli, G.; Bosco, M.; Carlone, A.; Dalpozzo,
R.; Locatelli, M.; Melchiorre, P.; Sambri, L. J. Org. Chem. 2006, 71, 9580-
9588. (n) House, S. E.; Poon, K. W. C.; Lam, H.; Dudley, G. B. J. Org.
Chem. 2006, 71, 420-422. (o) Li, B.; Berliner, M.; Buzon, R.; Chiu, C.
K.-F.; Colgan, S. T.; Kaneko, T.; Keene, N.; Kissel, W.; Le, T.; Leeman,
K. R.; Marquez, B.; Morris, R.; Newell, L.; Wunderwald, S.; Witt, M.;
Weaver, J.; Zhang, Z.; Zhang, Z. J. Org. Chem. 2006, 71, 9045-9050. (p)
Aristegui, S. R.; El-Murr, M. D.; Golding, B. T.; Griffin, R. J.; Hardcastle,
I. R. Org. Lett. 2006, 8, 5927-5929. (q) Fatakopoulou, I.; Barbayianni, E.;
Constantinou-Kokotou, V.; Bornscheuer, U. T.; Kokotos, G. J. Org. Chem.
2007, 72, 782-786.
Our proposed reaction mechanism for the deprotection of
these ethers is shown in Scheme 1, which depicts the
Scheme 1. Proposed Mechanism for the Acid-Mediated
Deprotection of Aromatic Ethers
(5) (a) For review, see: Ley, S. V.; Baxendale, I. R.; Bream, R. N.;
Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815-
4195. (b) Petchmanee, T.; Ploypradith, P.; Ruchirawat, S. J. Org. Chem.
2006, 71, 2892-2895 and references cited therein (ref 1).
(6) (a) Kotecha, N. R.; Ley, S. V.; Montegani, S. Synlett 1992, 395-
398. (b) Mayer, A. A.; Murphy, B. P. Synth. Commun. 1985, 15, 423-
429. For compound 2, see refs 4l and 4k. See the Supporting Information.
(7) Surface area of silica (Silicycle) is 500 m2/g while that of Amberlyst-
15 (Fluka) is 45 m2/g.
2638
Org. Lett., Vol. 9, No. 14, 2007

protonated intermediate 8, the desired product vanillin 9, the
carbocation resulting from the C-O bond cleavage 10, and
the byproducts 11-13 arising from the carbocation. Com-
pounds 11 and 12 were formed via Friedel-Crafts-type
C-alkylation reactions of 10 with vanillin (at the position
ortho to the hydroxy group) and toluene, respectively, while
olefins 13 were formed via loss of a proton on the carbon
adjacent to the carbocation. The overall reaction time may
not necessarily reflect the stability of carbocation generated
from the C-O aryl bond cleavage but rather the overall
combined rates of the C-O aryl bond cleavage and quench-
ing of the resulting carbocation.
when PTS-Si was used. The benzyl group in 15 was
selectively removed while the isopropyl group remained
virtually intact, furnishing 18 in moderate 58-60% yield.
Such preference could arise from the difference in the rate
of deprotection or the chelation provided by the adjacent
carbonyl group of the ester.8 In fact, when compound 16
was subjected to deprotection conditions, the isopropyl group
ortho to the methyl ester was selectively and cleanly
deprotected over the other at the para position, clearly
suggesting the importance of the chelation effect. Only a
small amount of byproducts 19 or 20 was detected.
Good selectivity could also be observed when similar or
different protecting groups are present in the same molecule
but on different aromatic rings. The unsaturated enone of
the chalcone system in 21 (Figure 1) seemed incompatible
These vanillin ethers were next investigated for their
competitive deprotection. As a model, the PMB ether of
vanillin 5 was employed for selective deprotection either
when mixed in equimolar amounts with the isopropyl ether
1 or with benzyl ether 4 in the presence of Amberlyst-15.
Good to excellent selectivity could be observed and the
results are summarized in Table 2. Between 1 and 5, lowering
Table 2. Competitive Deprotection of Vanillin Ether 5 in the
Presence of 1 or 4a
Figure 1. Chalcones and chalcone-derived compounds 21-24.
with the reaction conditions as its deprotection reaction gave
only low yields (13-22%) of 22. However, when the
unsaturated enone was completely reduced to aliphatic chain
in 23, the isopropyl group was smoothly removed, giving
the corresponding product 24 in 93% yield.
In addition, selective deprotections in the more function-
alized nitroalkane compounds 25-309 with Amberlyst-15
or PTS-Si occurred smoothly, furnishing the products 31a-f
in good yields (up to 91%) along with the bis-deprotected
byproduct 32.10 Table 4 summarizes the results of our
investigation. PMB was selectively removed over benzyl,
isopropyl, and allyl groups.
a Unless otherwise noted, equimolar amounts of ethers were used. The
reactions were allowed to proceed until one of the two ethers was completely
consumed. b The acid employed was Amberlyst-15. c Isolated combined
yield of vanillin mainly from the deprotection of 5, with varying amounts
of vanillin from partial deprotection of 1 or 4. d Isolated yield of the
remaining ether.
The isopropyl groups on the biaryl system as part of the
allocolchicine skeleton 33 and 3411 (Scheme 2) could be
smoothly deprotected to the corresponding products 35 (68%
and 69% yields with Amberlyst-15 and PTS-Si, respectively)
and 36 (78% and 75% yields with Amberlyst-15 and PTS-
Si, respectively) without the need for column chromatogra-
phy on silica otherwise required for purifying the crude
products with AlCl3.12
In summary, we have developed a general and effective
method for cleaving the C-O aryl bond using Amberlyst-
15 and PTS-Si. The rate of C-O aryl bond cleavage under
these reaction conditions was tert-butyl > PMB > di- and
temperature resulted in much greater selectivity while
requiring longer reaction time. The amount of acid used did
not seem to affect the selectivity. Similar results were
observed between 4 and 5.
We next investigated the removal of similar as well as
different protecting groups simultaneously present on the
same aromatic ring in compounds 14-16 which were
synthesized according to the standard procedures.6 As shown
in Table 3, use of solid-supported acids provided good
selectivity in the removal of protecting groups.
(8) Demyttenaere, J.; Van Syngel, K.; Markusse, A. P.; Vervisch, S.;
Debenedetti, S.; De Kimpe, N. Tetrahedron 2002, 58, 2163-2166.
(9) See the Supporting Information for their preparation.
(10) See the Supporting Information for its structure.
(11) (a) Besong, G.; Jarawicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle,
F. T. J. Org. Biomol. Chem. 2006, 4, 2193-2207. (b) Leblanc, M.; Fagnou,
K. Org. Lett. 2005, 7, 2849-2852. (c) Seganish, W. M.; DeShong, P. Org.
Lett. 2006, 8, 3951-3954.
(12) Deprotection of the isopropyl group(s) in 33 and 34 with AlCl3
furnished 35 in 71% and 36 in 70% yields, respectively.
Isopropyl ether of compound 14 was preferentially re-
moved over the isopropyl ester in moderate to good yields
to give compound 17. Significantly higher yield was obtained
Org. Lett., Vol. 9, No. 14, 2007
2639

Table 3. Selective Deprotection of Aromatic Ethers 14-16a
a Unless otherwise noted, the reactions were performed with 0.6 equiv of acids with no methanol added as additive. Solid-supported acids were removed
when starting materials were completely consumed as evident by tlc. b A ) Amberlyst-15; B ) PTS-Si. c C-Benzylated byproduct 19 was isolated in 13%
yield and 11% yield when Amberlyst-15 and PTS-Si were employed, respectively. d Methanol (4 equiv) was added as additive. e Compound 20 was isolated
in 7% yield and 2% yield when Amberlyst-15 and PTS-Si were employed, respectively.
trimethoxylated benzyl > benzyl > allyl > isopropyl groups,
which reflects both the stability of the carbocations and their
reactivity toward quenching. Substoichiometric or stoichio-
metric amounts of acids are generally required to effectively
Scheme 2. Deprotection of Isopropyl Groups on the Biaryl
Table 4. Selective Deprotection of Chalcone-Derived Aromatic
Ethers 25-30 to Products 31a-f
System of the Allocolchicine Skeleton
a
cleave the aromatic ethers under relatively mild reaction
conditions. Immobilization of acids on the solid supports
provides good to excellent selectivity in the removal of
protecting groups even when they were simultaneously
present in the same molecule. Generality and selectivity of
the solid-supported acids in the deprotection of aromatic
ethers should be applicable in devising strategies for
introducing and removing protecting groups in complex
syntheses and thus should prove useful in protecting group
manipulation.
Acknowledgment. Financial support from the Thailand
Research Fund (TRF) for S.R. and P.P. (DBG4780006),
PERCH-CIC for P.C., and the NSF-REU (INT-0123857) for
D.R.B. is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a 1.1 equiv of Amberlyst-15 or PTS-Si in PhMe at 65 °C for 1-3 h.
b Isolated yields (yields with Amberlyst-15, yields with PTS-Si). c 23% of
32 was obtained. d 5% of 32 was obtained.
OL070781+
2640
Org. Lett., Vol. 9, No. 14, 2007