Iron(III) tosylate-catalyzed deprotection of aromatic acetals in water

Article abstract of DOI:10.1016/j.tetlet.2010.05.112

The deprotection of aromatic as well as conjugated acetals and ketals in water is catalyzed by iron(III) tosylate (1.0-5.0 mol %). Iron(III) tosylate is an inexpensive and readily available catalyst. The use of water, the most environmentally benign solvent, makes this procedure especially attractive for acetal deprotection.

Full text of DOI:10.1016/j.tetlet.2010.05.112

Tetrahedron Letters 51 (2010) 3969–3971
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Tetrahedron Letters
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Iron(III) tosylate-catalyzed deprotection of aromatic acetals in water
*
Margaret E. Olson, James P. Carolan, Michael V. Chiodo, Phillip R. Lazzara, Ram S. Mohan
Laboratory for Environmentally Friendly Organic Synthesis, Department of Chemistry, Illinois Wesleyan University, Bloomington, IL 61701, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The deprotection of aromatic as well as conjugated acetals and ketals in water is catalyzed by iron(III)
tosylate (1.0–5.0 mol %). Iron(III) tosylate is an inexpensive and readily available catalyst. The use of
water, the most environmentally benign solvent, makes this procedure especially attractive for acetal
deprotection.
Received 8 May 2010
Revised 24 May 2010
Accepted 24 May 2010
Available online 27 May 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Deprotection
Acetals
Iron(III) tosylate
Water
The deprotection of acetals is an important step in organic syn-
thesis due to the wide application of acetals, especially in the
course of a total synthesis.1 Hence, many reagents have been
developed for this purpose.2 Considerable efforts have also been di-
rected toward developing mild and selective methods for acetal
deprotection.3 However, many of the reagents employed for this
purpose are corrosive and often toxic. Our continued interest in
developing environmentally friendly synthetic methodology
prompted us to investigate a mild and catalytic method for the
deprotection of acetals utilizing inexpensive, commercially avail-
able reagents. Herein we wish to report that iron(III) tosylate4 is
an efficient, inexpensive, and easy to handle catalyst for the depro-
tection of a wide range of aromatic acetals. Iron(III) tosylate is
commercially available as the hexahydrate and was used as such.
In spite of the lack of solubility of most organic compounds in
water, the low cost, easy availability, and non-flammability of
water as well as the observation of unexpected rate accelerations
have led to an increasing number of organic reactions being carried
out in water.5
The results of this study are summarized in Table 1. Preliminary
studies were conducted in aqueous THF but gratifyingly, subse-
quent attempts in water proved successful. As can be seen from
Table 1, a wide range of aromatic acetals and ketals underwent
smooth deprotection to give the corresponding carbonyl com-
pound in good to excellent yields. In most cases, the crude product
was found to be >98% pure by 1H and 13C NMR spectroscopy, thus
avoiding the need for expensive silica gel chromatographic purifi-
cation. Although iron(III) tosylate is water soluble, the substrates
shown in Table 1 are all insoluble in water, and hence the reactions
were carried out by stirring a suspension of the substrate in water.
Under the reaction conditions, it was possible to cleave an acetal
(entry 9) in the presence of
a tert-butyldimethylsilyl ether
(TBDMS).6 Such chemoselectivity is especially useful in the course
of a total synthesis where selective deprotection of protecting
groups is often necessary. The trityl group did not survive the reac-
tion conditions (entry 10) although it was necessary to carry out
the reaction in CH3OH/H2O (8:2, v/v).
Deprotection of aliphatic acetals was not as successful using
these reaction conditions. For example, when the dimethyl acetal
of dodecanal was subjected to the reaction conditions, less than
50% dodecanal formed after 22 h at reflux temperature. The depro-
tection of the dimethyl acetal of dodecanal was also attempted
with 5.0 mol % p-TsOH in H2O (pH ꢀ2) and in this case no dodeca-
nal formed after 22 h at reflux.
Although detailed mechanistic studies were not carried out, a
few points merit comment. The deprotection reactions were either
not successful or were incomplete in the absence of the catalyst.
The observation that a solution of iron tosylate in water is acidic
(pH ꢀ2) suggests that the p-TsOH might be an active catalyst,
though the role of Fe3+ as a Lewis acid cannot be ruled out. The
use of Fe(OTs)3 is still preferable to p-TsOH because the latter com-
pound is highly toxic and its handling poses a health hazard.7
In summary, a mild method for the deprotection of aromatic as
well as conjugated acetals and ketals catalyzed by iron(III) tosylate
in H2O has been developed.
Two representative procedures are given here (Table 1, entry 5): A
mixture of the dimethylacetal of p-anisaldehyde (0.5049 g,
2.77 mmol) in H2O (5.0 mL) was stirred at room temperature as
Fe(OTs)3Á6H2O (0.0188 g, 0.0277 mmol, 1.0 mol %) was added. The
* Corresponding author. Tel.: +1 309 556 3829; fax: +1 309 556 3864.
E-mail address: rmohan@iwu.edu (R.S. Mohan).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.05.112

3970
M. E. Olson et al. / Tetrahedron Letters 51 (2010) 3969–3971
Table 1
Deprotection of aromatic and conjugated acetals in water catalyzed by Fe(OTs)3Á6H2O
n
O
.
O
Fe(OTs)3 6H2O (1.0-5.0 mol%)
O
R3O OR3
R1 R2
or
H2O
R1
R2
R1 R2
n = (1 or 2)
R3 = Me or Et
Entry
Acetala
Catalyst (mol %)
Temp
Timeb
Yieldc,d (%)
1
2
3
4
5
6
p-ClC6H4CH(OMe)2
m-BrC6H4CH(OEt)2
o-BrC6H4CH(OEt)2
p-HOCC6H4CH(OEt)2
p-CH3OC6H4CH(OMe)2
p-Me2NC6H4CH(OMe)2
1.0
5.0
5.0
2.5
1.0
1.0
rt
19 h
1 h
2.5 h
16 h
1 h
84
95
Reflux
Reflux
rt
rt
rt
86
77e
88e
94
45 min
CH(OMe)2
Ph
7
1.0
rt
4 h
96
CH3
CH(OMe)2
8
1.0
rt
2 h
89e
H3C
CH3
9
p-tBuMe2SiOC6H4CH(OMe)2
2.0
5.0
rt
45 min
4 h
92f
O
Br
10
Reflux
78g
O
OCPh3
O
O
12
13
5.0
5.0
Reflux
Reflux
40 min
1 h
98
73
O2N
O
O
Cl
O
O
14
5.0
Reflux
40 min
92
Br
O
O
15
16
5.0
5.0
Reflux
Reflux
1 h
1 h
94
97
O2N
O
O
Cl
O
O
17
5.0
Reflux
1 h
81
OCH3
O
18
19
O
5.0
5.0
Reflux
Reflux
1 h
1 h
83
92
H3C
O
O
H3CO

M. E. Olson et al. / Tetrahedron Letters 51 (2010) 3969–3971
3971
Table 1 (continued)
Entry
Acetala
Catalyst (mol %)
5.0
Temp
Timeb
1 h
Yieldc,d (%)
O
20
Reflux
98e
O
H3CO
H3C
O
21
22
5.0
5.0
5.0
Reflux
Reflux
Reflux
1 h
86
O
O
1 h
74
O
O
92e
O
23
1.25 h
Acetals were either purchased commercially or synthesized by a previously reported method.8
The progress of the reaction was followed by GC, TLC or 1H NMR.
Refers to yield of the isolated product. The crude products from acyclic acetals were found to be P98% pure and hence further purification was deemed unnecessary. It
a
b
c
was necessary to purify crude products from a few cyclic acetals (entries 14, 15, 17, 21 and 22) by flash chromatography.
d
All products are commercially available and were characterized by 1H and 13C NMR spectroscopy, and by GC analysis.
Product was 97% pure by GC analysis.
The product was 4-(tert-butyldimethylsilyloxy)benzaldehyde.
The reaction was carried out in CH3OH/H2O (8:2, v/v). The crude product was purified by dissolving in ether and extraction with aqueous 2 M NaOH, followed by
e
f
g
acidification with aqueous 3 M H2SO4. The product was 5-bromo-2-hydroxybenzaldehyde.
T.; Kondoh, H.; Honda, T.; Ishizone, H.; Suzuki, Y.; Mori, W. Chem. Lett. 1989, 18,
progress of the reaction was monitored by GC. After 1 h, the reac-
901; Bi(NO3)3Á5H2O: (f) Eash, K. J.; Pulia, M. S.; Wieland, L. C.; Mohan, R. S. J. Org.
tion mixture was extracted with EtOAc (2 Â 20 mL). The organic
Chem. 2000, 65, 8399; BiCl3: (g) Sabitha, G.; Babu, R. S.; Reddy, E. V.; Yadav, J. S.
layer was washed with aqueous saturated NaHCO3 (15 mL), aque-
ous saturated NaCl (15 mL), dried (Na2SO4), and concentrated on a
rotary evaporator to yield 0.3327 g (88%) of p-anisaldehyde as a
clear liquid. The product was determined by GC analysis, and 1H
and 13C NMR spectroscopy to be 97% pure.
Chem. Lett. 2000, 29, 1074; (h) Eshghi, H.; Rahimizadeh, M.; Saberi, S. Catal.
Commun. 2008, 9, 2460; MW-assisted Er(OTf)3: (i) Procopio, A.; Gaspari, M.;
Nardi, M.; Oliverio, M.; Romeo, R. Tetrahedron Lett. 2008, 49, 1961; CF3COOH: (j)
Li, W.; Li, J.; Wu, Y.; Fuller, N.; Markus, M. A. J. Org. Chem. 2010, 75, 1077.
3. TiCl4: (a) Balme, G.; Goré, J. J. Org. Chem. 1983, 48, 3336; FeCl3Á6H2O on silica gel:
(b) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem. 1986, 51, 404; Ph3P/
CBr4: (c) Johnstone, C.; Kerr, W. J.; Scott, J. S. J. Chem. Soc., Chem. Commun. 1996,
341; CeCl3: (d) Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.; Sambri, L. J. Org.
Chem. 1997, 62, 4183; FeCl3Á6H2O: (e) Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing,
G. J.; Magrath, J. J. Org. Chem. 1997, 62, 6684; TMSN(SO2F)2: (f) Kaur, G.; Trehan,
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Angew. Chem., Int. Ed. 1999, 38, 3207; Bi(OTf)3Á4H2O: (h) Carrigan, M. D.; Sarapa,
D.; Smith, R. C.; Wieland, L. C.; Mohan, R. S. J. Org. Chem. 2002, 67, 1027; (i)
Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio, A.; Tagarelli, A.; Sindona, G.;
Bartoli, G. J. Org. Chem. 2002, 67, 9093; b-Cyclodextrin: (j) Krishnaveni, N. S.;
Surendra, K.; Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68,
2018; I2: (k) Sun, J.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. Org. Chem.
2004, 69, 8932; TESOTf-2,6-lutidine: (l) Fujioka, H.; Sawama, Y.; Murata, N.;
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CuSO4/NaI: (m) Bailey, A. D.; Cherney, S. M.; Anzalone, P. W.; Anderson, E. D.;
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(Table 1, entry 9): A mixture of tert-butyl(4-(dimethoxymeth-
yl)phenoxy)dimethylsilane (0.2109 g, 0.75 mmol) in H2O (4.0 mL)
was stirred at room temperature as Fe(OTs)3Á6H2O (0.0101 g,
0.0149 mmol, 2.0 mol %) was added. The progress of the reaction
was monitored by GC. After 45 min, the reaction mixture was ex-
tracted with EtOAc (2 Â 20 mL). The organic layer was washed
with aqueous saturated NaHCO3 (10 mL), aqueous saturated NaCl
(10 mL), dried (Na2SO4), and concentrated on a rotary evaporator
to yield 0.1617 g (92%) of 4-(tert-butyldimethylsilyloxy)benzalde-
hyde as a clear liquid. The product was determined by GC analysis
and 1H NMR to be 99% pure.
Acknowledgments
4. For examples of use of Fe(OTs)3 as a catalyst in organic synthesis, see (a)
Mansilla, H.; Afonso, M. M. Synth. Commun. 2008, 38, 2607; (b) Spafford, M. J.;
Anderson, E. D.; Lacey, J. R.; Palma, A. C.; Mohan, R. S. Tetrahedron Lett. 2007, 48,
8665; (c) Bothwell, J. M.; Angeles, V. V.; Carolan, J. P.; Olson, M. E.; Mohan, R. S.
Tetrahedron Lett. 2010, 51, 1056.
5. (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; Wiley-Interscience
Publication: New York, 1997; For a review on organic chemistry in water, see (b)
Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
The authors gratefully acknowledge the funding from the Na-
tional Science Foundation for a RUI (Research in Undergraduate
Institutions) Grant (# 0650682) awarded to R.S.M.
References and notes
6. We have recently reported (see Ref. 4c) the iron(III) tosylate catalyzed
deprotection of tert-butyldimethylsilyl ethers in CH3OH as a solvent. However,
in this case no deprotection was observed in water as a solvent.
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toluenesulfonic acid. Iron(III) tosylate has
a HMIS (hazardous material
identification system) rating of 2 (moderate hazard) while p-toluenesulfonic
acid has a HMIS rating of 3 (serious hazard).
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