A remarkable iodine-catalyzed protection of carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2005.01.176

We report here a remarkably simple molecular iodine-catalyzed protection method for various carbonyl compounds as ketals in a general reaction. The iodine-catalyzed reaction of mandelic acid and lactic acid with several aldehydes has furnished a highly diastereoselective synthesis of cis and trans dioxolanones.

Full text of DOI:10.1016/j.tetlet.2005.01.176

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2341–2343
A remarkable iodine-catalyzed protection of carbonyl compounds
Bimal K. Banik,* Marin Chapa, Jocabed Marquez and Magda Cardona
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78541, USA
Received 1 December 2004; revised 24 January 2005; accepted 26 January 2005
Abstract—We report here a remarkably simple molecular iodine-catalyzed protection method for various carbonyl compounds as
ketals in a general reaction. The iodine-catalyzed reaction of mandelic acid and lactic acid with several aldehydes has furnished a
highly diastereoselective synthesis of cis and trans dioxolanones.
Ó 2005 Published by Elsevier Ltd.
Protection of carbonyl groups plays an important role in
organic, medicinal, and carbohydrate chemistry as well
as the chemistry of drug design.1 Tremendous efforts
have been made to search for a suitable protective group
for carbonyl compounds. In spite of these efforts, pro-
tection as 1,3-dioxolane remains the most practical
choice.2 The reason for this choice obviously is the sim-
plicity of the protection procedure and ready availability
of the starting reagents. In addition, these ketal-type of
compounds can be used for the total synthesis of natural
products and therefore, serve as valuable intermediates
in organic synthesis. In general, the protection method
requires protic acids, Lewis acids, or acidic catalysts.
The limitations are nonchemoselectivity and incompati-
bility with the other functional groups present in the
molecule. Two of the most important shortcomings of
the existing protection methods are the long reaction
time and conditions that require a high temperature
along with a stoichiometric amount of reagents. Many
of the existing methods often use toxic and corrosive re-
agents, for example, titanium tetrachloride, borontrifluo-
ride etherate, trifluoromethane sulfonic acid, and
trifluoromethane sulfonic anhydride.2g,3–5 Furthermore,
lanthanides and other metal catalysts have been found
to be excellent in the selective ketalization of carbonyl
compounds under mild conditions. Lanthanides are,
however, substrate selective, and a general protection
method cannot be achieved using these catalysts.2g,3
Therefore, an alternative method that can overcome
these drawbacks and be applied to a number of sub-
strates in a catalytic process is highly desirable.
We have studied iodine-catalyzed organic transforma-
tions.6 Because iodine-catalyzed reaction has consider-
able promise, our focus has extended to the protection
of carbonyl groups. This report gives a preliminary ac-
count of our preparation of ketals mediated by molecu-
lar iodine. The reaction of mandelic acid and lactic acid
with several aldehydes under an identical condition has
furnished a highly diastereoselective synthesis of cis and
trans dioxolanones.
Several ketals were prepared using carbonyl com-
pounds and ethylene glycol in the presence of iodine
(5 mol%) and the data are shown in Table 1. Aliphatic
aldehydes and ketones were extremely good substrates
for this purpose. The yields with the aromatic aldehydes
and benzylic ketones were satisfactory (Scheme 1).
Realizing the versatility of our method of iodine-cata-
lyzed protection of the carbonyl groups, we envision
that this method can provide an easy access to optically
active dioxolanones. Notably, many examples of both
amino acids and hydroxy carboxylic acids are now avail-
able in enantiomeric forms. The scope of this reaction is
further increased by the fact that optically active amino
acids can be converted to hydroxy acids with retention
of configuration. These types of compounds are fre-
quently used as the starting materials for the synthesis
of many other natural and nonnatural compounds.2i,7
In principle, the reaction of optically active hydroxy
acids with aldehydes during ketalization can produce
two isomeric compounds.
In conformity with this hypothesis, iodine-catalyzed
reaction of mandelic acid and lactic acid with several
aldehydes produced a highly diastereoselective mixture
of cis and trans dioxolanones (Scheme 2). The isomer
*
Corresponding author. Tel.: +1 956 3808741; fax: +1 956 384
5006; e-mail: banik@panam.edu
Undergraduate research participants; contributed equally.
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.01.176

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B. K. Banik et al. / Tetrahedron Letters 46 (2005) 2341–2343
Table 1. Protection of carbonyl compounds as ketal in the presence of
iodine
THF. Interestingly, the stereochemistry of the products
remains identical under various reaction conditions. In
addition, the solvent does not seem to play a role in
the success of the reaction or in dictating the stereo-
chemistry of the products (Scheme 2).
Entry Carbonyl compounds
Time (h) Yield (%)a
1
Cyclohexanone
2-Methyl-cyclohexanone
4-Methyl-cyclohexanone
16
16
16
90
75
90
88
88
70
50
50
40
30
80
70
50
65
65
75
88
90
90
2
3
The present iodine-catalyzed reaction does not proceed
in the absence of iodine. Protection also failed in the
presence of iodine (1%) and potassium carbonate mix-
ture (10%). This experiment ruled out the possibility of
a complexation role of the molecular iodine to the carb-
onyl group. This indicates that hydroiodic acid was
the actual catalyst in this reaction. However, reaction
in the presence of catalytic amounts of hydroiodic acid
produced ketals in very low yield. Precise control of
the acidity in a small-scale reaction with hydroiodic acid
or other strong acids is extremely difficult. Moreover,
our method can be applied to a large-scale reaction.
Although, a smaller amount of iodine (0.1 mol%) can
be used successfully, a higher proportion of iodine
(5 mol%) can accelerate the reaction.
4
3,3,5,5-Tetramethyl-cyclohexanone 16
5
4-tert-Butyl-cyclohexanone
2-Methyl-cyclopentanone
Acetophenone
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
6
7
8
4-Methoxy-acetophenone
Benzylacetone
9
10
11
12
13
14
15
16
17
18
19
b-Tetralone
2-Heptanone
Benzaldehyde
2-Nitro-benzaldehyde
2-Bromo-benzaldehyde
Cinnamaldehyde
p-Anisaldehyde
Decanal
Butanal
Propanal
a The yield was calculated after 16 h reaction in each case.
In conclusion, our iodine-catalyzed protection of carb-
onyl groups is general, mild, novel, cost-effective, and
convenient from a practical point of view.8 The asym-
metric and diastereoselective version of this method
adds significant value. At present, we are exploring
other possibilities for this reaction, the results of which
will be reported in due course.
R1
R2
O
O
R1
R2
HO(CH2)2OH
2 (5 mol %)
O
I
Scheme 1.
O
O
HO
HO
Acknowledgements
R1
R2
O
O
R1
R2
I2(5mol%)
THF
O +
'
R
We gratefully acknowledge the partial financial support
for this research from The Robert A. Welch Foundation
(BG-0017) departmental grant and The University of
Texas-Pan American.
'
R
Scheme 2.
ratio was calculated by a comparison of known authen-
tic samples and NMR spectra. Brønsted acid-catalyzed
ketalization with azeotropic removal of water and Lewis
acid-mediated reaction also produced a similar mixture
of isomers. In addition, a recent study showed that scan-
dium trifluoromethanesulfonimide-mediated reactions
are believed to be solvent dependent. Moreover, the suc-
cess in most cases depends on the precise azeotropic re-
moval of water from the reaction media. The ratios of
the cis and trans isomers described above were depen-
dent on the temperature of the reaction. (Table 2) In
contrast, our iodine-catalyzed reaction is not dependent
on the temperature of the reaction media and proceeds
exceedingly well at room to reflux temperature in
References and notes
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Table 2. Diastereoselective synthesis of ketal
Entry
Carbonyl compounds
R0
Yield (%)
cis/trans
1
2
3
4
5
6
7
Cyclohexanone
Pivaldehyde
Pivaldehyde
Ph
Ph
65
9089/11
85
—
CH3
Ph
84/16
86/14
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5067/33
4081/19
CH3
Hydrocinnamaldehyde
Butyraldehyde
CH/230 5080
Ph 86

B. K. Banik et al. / Tetrahedron Letters 46 (2005) 2341–2343
2343
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8. General ketalization procedure: The carbonyl compound
(1 mmol) was dissolved in ethylene glycol (1 mL), and
iodine (0.05 mmol) was added to the solution with stirring.
After the starting material was consumed as indicated by
TLC, diethyl ether (10mL) was added. The reaction
mixture was washed with Na2S2O3 (5%, 5 mL), washed
with saturated NaHCO3, dried over Na2SO4 and the
solvent gets evaporated. Finally, the pure products were
obtained via purification through basic alumina using ethyl
acetate–hexane (10:90) as the solvent.
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