A simple and efficient chemoselective method for the catalytic deprotection of acetals and ketals using bismuth trifiate

Article abstract of DOI:10.1021/jo016180s

Bismuth triflate is a highly efficient catalyst (0.1-1 mol %) for the deprotection of acetals and ketals. The procedure is very facile and selective for acetals derived from ketones and conjugated aldehydes. tert-Butyldimethylsilyl ethers are stable to the reaction conditions. The highly catalytic nature of bismuth triflate and the use of a relatively nontoxic solvent system (THF/H₂O) make this procedure particularly attractive for large-scale synthesis.

Full text of DOI:10.1021/jo016180s

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J . Org. Chem. 2002, 67, 1027-1030
1027
Sch em e 1
A Sim p le a n d Efficien t Ch em oselective
Meth od for th e Ca ta lytic Dep r otection of
Aceta ls a n d Keta ls Usin g Bism u th Tr ifla te
Marc D. Carrigan, Dusan Sarapa, Russell C. Smith,
Laura C. Wieland, and Ram S. Mohan*
Department of Chemistry, Illinois Wesleyan University,
Bloomington, Illinois 61701
rmohan@titan.iwu.edu
Received October 6, 2001
sulfonylation of arenes,8 Diels-Alder reactions,9 the aza-
Diels-Alder reaction,10 acylation of alcohols,11 epoxide
rearrangements,12 and acylal synthesis.13
We now wish to report that bismuth triflate in aqueous
tetrahydrofuran is a highly efficient catalyst for the
selective deprotection of acetals derived from ketones and
conjugated aldehydes (Scheme 1).
Abstr a ct: Bismuth triflate is a highly efficient catalyst
(0.1-1 mol %) for the deprotection of acetals and ketals. The
procedure is very facile and selective for acetals derived from
ketones and conjugated aldehydes. tert-Butyldimethylsilyl
ethers are stable to the reaction conditions. The highly
catalytic nature of bismuth triflate and the use of a relatively
nontoxic solvent system (THF/H2O) make this procedure
particularly attractive for large-scale synthesis.
The experimental procedure is simple and involves
stirring the substrate as a solution in THF/H2O (80:20,
v/v) in the presence of bismuth triflate. To test the
efficiency of the catalyst, deprotection of several acetals
and ketals (entries 1, 6, 11, 16, and 17) was attempted
with as little as 0.1 mol % catalyst. In all cases, the
corresponding carbonyl compound was obtained in high
yield. The highly catalytic nature of this system makes
this procedure particularly attractive for large-scale
synthesis. The effective large-scale utilization of this
system is demonstrated by the successful deprotection
of acetophenone dimethyl acetal (entry 11b) and citral
dimethyl acetal (entry 6b) on a 10-g scale. Only ap-
proximately 30 mg of the catalyst is needed to effect
deprotection of acetals on this scale. Bismuth triflate is
not commercially available, but can be easily synthesized
as the tetrahydrate in the laboratory following a litera-
ture method.14 It is insoluble in common organic solvents
and is used as a suspension. It is a noncorrosive solid
and has a good shelf life. THF/H2O was found to be the
best solvent system for the deprotection of acetals. Less
satisfactory results were obtained in aqueous methanol
and CH2Cl2 saturated with water. The results of this
study are summarized in Table 1.
Acetals are frequently used to protect carbonyl com-
pounds in the course of a total synthesis, and hence
several reagents have been developed for their deprotec-
tion.1,2 Considerable effort has also been directed toward
developing mild, selective methods for acetal deprotec-
tion.3 Recently, we reported that bismuth(III) nitrate
pentahydrate (25 mol %) in CH2Cl2 is an efficient reagent
for the deprotection of acyclic O,O-acetals derived from
ketones and conjugated aldehydes.4 Cyclic acetals and
TBDMS ethers are not affected by bismuth nitrate.
Bismuth compounds are of interest because of their low
toxicity and low cost.5,6 A search for a bismuth-based
reagent with greater catalytic activity that also avoided
the use of a chlorinated solvent formed the basis of this
study and led to the development of bismuth triflate as
a catalyst for acetal deprotection. Bismuth triflate has
been used as a catalyst for Friedel-Crafts Acylations,7
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley and Sons: New York, 1999. (b) Hanson,
J . R. Protecting Groups in Organic Synthesis, 1st ed.; Blackwell Science,
Inc: Malden, MA, 1999. (c) Kocienski, P. J . Protecting Groups, 1st ed.;
Georg Thieme Verlag: Stuttgart, 1994.
(2) (a) p-TsOH/acetone: Colvin, E. W.; Raphael, R. A.; Roberts, J .
S. J . Chem. Soc. Chem. Commun. 1971, 858. (b) Amberlyst-15/aqueous
acetone: Coppola, G. M. Synthesis 1984, 1021. (c) 50% trifluoroacetic
acid in CHCl3-H2O: Ellison, R. A.; Lukenbach, E. R.; Chiu, C.-W.
Tetrahedron Lett. 1975, 499. (d) Aqueous DMSO: Kametani, T.;
Kondoh, H.; Honda, T.; Ishizone H.; Suzuki, Y.; Mori, W. Chem. Lett.
1989, 901. (e) LiBF4: Lipshutz, B. H.; Harvey, D. F. Synth. Commun.
1982, 12, 267.
(3) (a) Marko´, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J .-
M.; Quesnel, Y.; Vanherck, J .-C. Angew. Chem., Int. Ed. 1999, 38, 3207.
(b) J ohnstone, C.; Kerr, W.; Scott, J . Chem. Commun. 1996, 341. (c)
Balme, G.; Gore´, J . J . Org. Chem. 1983, 48, 3336. (d) Kim, K. S.; Song,
Y. H.; Lee, B. H.; Hahn, C. S. J . Org. Chem. 1986, 51, 404. (e) Kaur,
G.; Trehan, A.; Trehan, S. J . Org. Chem. 1998, 63, 2365.
(4) Eash, K. J .; Pulia, M. S.; Wieland, L. C.; Mohan, R. S. J . Org.
Chem. 2000, 65, 8399.
(5) (a) Reglinski, J . In Chemistry of Arsenic, Antimony and Bismuth;
Norman, N. C., Ed.; Blackie Academic and Professional. New York,
1998; pp 403-440. (b) Marshall, J . A. Chemtracts 1997, 1064-1075.
(c) Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249-267.
(6) Organobismuth Chemistry; Suzuki, H., Matano, Y., Eds.;
Elsevier: Amsterdam, 2001.
Dialkyl acetals derived from aromatic aldehydes under-
went smooth deprotection at room temperature. Benzal-
dehyde dimethyl acetal (entry 1), piperonal dimethyl
acetal (entry 2), 4-chlorobenzaldehyde dimethyl acetal
(entry 3), and terephthalaldehyde mono-(diethyl acetal)
(entry 4) were all converted to the corresponding alde-
hyde in good yields. Similar results were obtained with
the conjugated acetals derived from cinnamaldehyde
(8) Repichet, S.; Le Roux, C.; Hernandez, P.; Dubac, J . J . Org. Chem.
1999, 64, 6479.
(9) (a) Garrigues, B.; Gonzanga, F.; Robert, H.; Dubac, J . J . Org.
Chem. 1997, 62, 4880. (b) Robert, H.; Garrigues, B.; Dubac, J .
Tetrahedron Lett. 1998, 39, 1161.
(10) Laurent-Robert, H.; Garrigues, B.; Dubac, J . Synlett 2000, 1160.
(11) (a) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J . Angew.
Chem., Int. Ed. 2000, 39, 2877. (b) Carrigan, M. D.; Freiberg, D. F.;
Smith, R. C.; Zerth, H. M.; Mohan, R. S. Synthesis 2001, 2091.
(12) Bhatia, K. A.; Leonard, N. M.; Oswald, M. C.; Eash, K. J .;
Mohan, R. S. Tetrahedron Lett. 2001, 42, 8129.
(13) Carrigan, M. D.; Eash, K. J .; Oswald, M. C.; Mohan, R. S.
Tetrahedron Lett. 2001, 42, 8133.
(14) Labrouillere, M.; Le Roux, C.; Gaspard, H.; Laporterie, A.;
Dubac, J .; Desmurs, J . R. Tetrahedron Lett. 1999, 40, 285.
(7) (a) Labrouille`re, M.; Le Roux C.; Gaspard, H.; Laporterie, A.;
Dubac, J . Tetrahedron Lett. 1997, 38, 8871. (b) Repichet, S.; Le Roux,
C.; Dubac, J .; Desmure, J .-R. Eur. J . Org. Chem. 1998, 2743.
10.1021/jo016180s CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

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1028 J . Org. Chem., Vol. 67, No. 3, 2002
Notes
Ta ble 1. Dep r otection of Aceta ls a n d Keta ls in THF /H2O Usin g Bi(OTf)3‚xH2O

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Notes
J . Org. Chem., Vol. 67, No. 3, 2002 1029
Ta ble 1. (Con tin u ed )
a
b
All the products have been reported previously in the literature.4 Refers to yield of isolated product. c Crude product was >98%
pure (based on 1H NMR and 13C NMR spectra) and hence it was not purified further. Purified by trituration with cold hexanes. e Purified
d
by flash column chromatography. f Product was a mixture of SM (67%) and benzil (33%). g Work up was modified as follows: After removal
of THF, the residue was extracted with ether. Product was then isolated by extraction of the ether solution with 2 M aqueous NaOH
followed by acidification.
Sch em e 2
(entry 5) and citral (entry 6). Acetals derived from
nonconjugated aldehydes were more resistant to the
reagent. When the dimethyl acetal of heptanal (entry 7)
was subjected to the reaction conditions, almost no
heptanal (<2% based on 1H NMR) formed and the
starting material was recovered unchanged. Even after
the reaction mixture was heated at reflux for 24 h, >95%
of the starting material remained. However, both phenyl-
acetaldehyde dimethyl acetal (entry 8) and 2-phenyl-
propionaldehyde dimethyl acetal (entry 9) underwent
deprotection when heated at reflux. Acetals derived from
aromatic as well as aliphatic ketones (entries 10-12)
underwent smooth deprotection at room temperature.
The presence of a carbonyl group R to the acetal moiety
slowed the rate of deprotection. Thus the monacetal
derived from benzil underwent only partial deprotection,
even when heated at reflux (entry 13). Conjugation
with a triple bond accelerated the rate of the deprotection
of aldehyde acetals relative to unconjugated aldehyde
acetals, but not to the same degree as a double bond. The
diethyl acetal of phenylpropargyl aldehyde (entry 14) was
converted to phenylpropargyl aldehyde in good yield
when heated at reflux for 12 h.
was recovered in quantitative yield in all cases. However,
they underwent smooth deprotection under reflux condi-
tions. This is in contrast to results obtained using
bismuth(III) nitrate pentahydrate as a reagent for depro-
tection of acetals which proved to be ineffective for de-
protection of dioxolanes. Tetrahydropyranyl ether (entry
18) as well as tert-butyldimethylsilyl ethers derived from
both alcohols and phenols (entries 19 and 20) were
resistant to the reaction conditions. To demonstrate
the chemoselectivity of this reagent, the TBDMS ether
(entry 21) of 4-(diethoxymethyl)benzenemethanol was
prepared.4 We were able to remove the acetal group
without affecting the TBDMS group to yield 4-(tert-
butyldimethylsilyloxy)methylbenzaldehyde in a good yield
(Scheme 2).
Thus this method can be used to selectively deprotect
an acetal in the presence of a TBDMS group in a
multifunctional compound. While the trityl ether derived
Cyclic acetals did not undergo deprotection at room
temperature (entries 15-17), and the starting material

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1030 J . Org. Chem., Vol. 67, No. 3, 2002
Notes
from an alcohol proved resistant to the reagent (entry
22), deprotection of a trityl ether derived from a phenol
was observed. The bifunctional compound containing a
dioxolane and trityl-protected phenol moiety (entry 23)
was converted to the corresponding bromosalicyladehyde
in an excellent yield.
potassium carbonate, it appears that triflic acid is the
active catalyst in this system.
In conclusion, this paper describes the use of bismuth
triflate for the chemoselective deprotection of acetals
derived from ketones and conjugated aldehydes. The
advantages of this method are (1) the highly catalytic
nature of the reagent, (2) the observed selectivity, and
(3) the use of a relatively nontoxic solvent system.
Several control experiments were carried out in order
to gain some mechanistic insights. No reaction was
observed when the substrate was stirred as a solution
in THF/H2O in the absence of the catalyst, indicating that
the presence of bismuth triflate is necessary to cause
deprotection. A suspension of Bi(OTf)3‚xH2O in water is
acidic, and the aqueous layer from the workup was also
found to be acidic (pH 2). Deprotection of several acetals
(entries 1, 3, 4, 11, and 15) was attempted in THF/H2O
containing a few drops of triflic acid (approximately 2
mol %) instead of bismuth triflate. In all cases the corre-
sponding carbonyl compound was formed in comparable
yields. However, unlike bismuth(III) triflate which is a
noncorrosive solid, triflic acid is a corrosive liquid that
is difficult to handle even on a small scale. Deprotection
was also studied in a buffered medium to see if there
remained any Lewis acid catalytic effect.15 The depro-
tection of benzaldehyde dimethyl acetal (entry 1) and
acetophenone dimethyl acetal (entry 11) was carried
out with 1 mol % bismuth triflate in the presence of
(a) 2 mol % Proton-Sponge ([1,8-bis-dimethylamino]-
naphthalene)16 and (b) 5 mol % solid potassium carbon-
ate. Significant deprotection (>10%) did not occur in any
case, and the starting material was recovered in good
yields. If the deprotection was accelerated primarily by
complexation of the Lewis acid to the carbonyl group, one
would expect the added potassium carbonate to have
little effect on the rate of deprotection. However, since
signifcant deprotection does not occur in the presence of
Exp er im en ta l Section 17
Typ ica l P r oced u r e. A solution of (1,1-dimethoxyethyl)-
benzene (1.00 g, 6.02 mmol) (entry 11) in THF/H2O (8 mL of
THF, 2 mL of H2O) was stirred at room temperature as Bi(OTf)3‚
xH2O (4.0 mg, 6 × 10-3 mmol) was added. After 45 min, THF
was removed on a rotary evaporator, and the residue was
extracted with diethyl ether. The organic layer was washed with
10% aqueous NaHCO3 and saturated NaCl and dried (Na2SO4).
The solvent was removed on a rotary evaporator to yield 0.630
g (87%) of acetophenone that was determined to be >98% pure
by 1H and 13C NMR spectroscopy.
La r ge Sca le Dep r otection . A solution of citral dimethyl
acetal (10.0 g, 0.050 mol) (entry 6) in THF/H2O (80 mL of THF,
20 mL of H2O) was stirred at room temperature as Bi(OTf)3‚
xH2O (33.1 mg, 0.0504 mmol) was added. After 2 h, THF was
removed on a rotary evaporator, and the residue was extracted
with diethyl ether (2 × 40 mL). The organic layer was washed
with 10% aqueous NaHCO3 and saturated NaCl and dried (Na2-
SO4). The solvent was removed on a rotary evaporator to yield
7.17 g (93%) of citral that was determined to be >98% pure by
1H and 13C NMR spectroscopy. Based on GC and NMR analysis
of the product, it was concluded that no isomerization of the
double bond in citral acetal occurred during the deprotection.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from The National Science Foundation
(NSF-RUI grant, CHE0078881). We would also like to
thank Dr. Martin Hulce (Creighton University) for
useful discussions.
(15) The authors wish to thank an anonymous reviewer for useful
suggestions about possible mechanistic studies.
J O016180S
(16) Brezinski, B.; Grech, E.; Malarski, Z.; Sobczyk, L. J . Chem. Soc.,
Perkin Trans. 2 1991, 2, 857.
(17) For details of the general Experimental Section, see ref 4.