Simple and efficient chemoselective mild deprotection of acetals and ketals using cerium(III) triflate

Article abstract of DOI:10.1021/jo0260387

A new and chemoselective method for the cleavage of alkyl and cyclic acetals and ketals at room temperature in wet nitromethane by using catalytic cerium(III) trifluoromethane sulfonate is presented. The high yields, the observed selectivity, the very gentle reaction conditions, and the almost neutral pH make this procedure particularly attractive for multistep synthesis.

Full text of DOI:10.1021/jo0260387

TABLE 1. Dep r otection of 2-P h en yl-1,3-d ioxola n e by
Usin g Ce(OTf)3 in Va r iou s Exp er im en ta l Con d ition s
Sim p le a n d Efficien t Ch em oselective Mild
Dep r otection of Aceta ls a n d Keta ls Usin g
Cer iu m (III) Tr ifla te
†
†
†
Renato Dalpozzo, Antonio De Nino, Loredana Maiuolo,
,
†
†
Antonio Procopio,* Antonio Tagarelli,
Giovanni Sindona, and Giuseppe Bartoli
entry
Ce(OTf)3 (mol %)
solvent
THFa
CHCl3 a
t (h)
yield (%)
†
‡
1
2
3
4
5
6
30
30
30
30
30
15
15
15
6
6
6
60
25
80
98
17
73
Dipartimento di Chimica, Universit a` della Calabria,
a
CH3CN
I-87030 Arcavacata di Rende (CS), Italy, and Dipartimento
di Chimica Organica “A. Mangini”, viale Risorgimento 4,
I-40136 Bologna, Italy
CH3NO2 a
b
CH3NO2
CH3NO2 a
6
procopio@unical.it
a
Saturated with water. b Dry solvent.
Received J une 11, 2002
reported needs to reflux the reaction mixture for several
hours to deprotect the most resistant acetals and ketals
as 1,3-dioxolanes.
Herein, we reported a new mild efficient method for
the selective deprotection of acetal and ketal groups in
the presence of other protective groups by using
cerium(III) trifluoromethane sulfonate hydrate as a
Lewis acid catalyst.
Abstr a ct: A new and chemoselective method for the cleav-
age of alkyl and cyclic acetals and ketals at room temper-
ature in wet nitromethane by using catalytic cerium(III)
trifluoromethane sulfonate is presented. The high yields, the
observed selectivity, the very gentle reaction conditions, and
the almost neutral pH make this procedure particularly
attractive for multistep synthesis.
The deprotection of cyclic acetals and ketals as 1,3-
dioxolane was already described by using cerium(III)
Chemoselective transformation of polyfunctional mol-
ecules is a challenging problem in organic syntheses. The
selective protection/deprotection of carbonyl groups oc-
cupies a fundamental role in the multistep synthesis.
There are tens of protective groups that can be introduced
8
chloride heptahydrate in acetonitrile, a system previ-
9
ously used for cleavage of different protective groups.
The method does not use CeCl
3
2
‚7H O as catalyst, but as
1
reagent in 1.5 molar equiv, and it does not work properly
for acetals and ketals different from 1,3-dioxolane. Metal
parts of metal triflates are more cationic than those of
metal chlorides,10 and thus, we expected that cerium(III)
triflate was more Lewis acidic than cerium(III) chloride.
We tested cerium(III) triflate as Lewis acid for depro-
tection of acetals and ketals because the reagent is known
and removed by a variety of methods, but considerable
efforts are still directed toward developing efficient,
selective, and mild systems for both the introduction and
2
cleavage of many existing protective groups. Acetals and
ketals are frequently used to protect carbonyl compounds
and hence several reagents have been developed for their
deprotection in very smoothly conditions: CAN in neutral
3
4
h h
to fulfill the requirements of pK values (K ) hydrolysis
or mildly conditions, thiourea in EtOH/H
2
O, SmCl
3
/
TMSCl.5
constant) of 4.3-10.08 and WERK (water exchange rate
6
-1 -1
constant) greater than 3.2 × 10 M
s
for obtaining
In recent years, metal triflate mediated Lewis acid
catalysis has attracted enormous interest throughout the
sufficient activity as Lewis acid catalyst according to
6
Kobayashi et al. [Ce(OTf)
3
: pK
h
) 8.3; WERK ) 2.7 ×
scientific community. Bismuth triflate, for example, was
8
10
1
0 ].
reported to be a highly efficient Lewis catalyst for
deprotection of acetals and ketals in aqueous tetrahy-
Ce(OTf)
3
is not easily commercially available, but it
drofuran.7 A suspension of Bi(OTf)
acidic, and the aqueous layer from the workup was also
can be prepared in the laboratory in a straightforward
manner.11 Cerium(III) trifluoromethane sulfonate is a
noncorrosive white solid, and it can be stored under dry
3
‚xH
2
O in water is
found to be acidic (pH ) 2). Moreover, the method
*
To whom correspondence should be addressed. Tel: +39 984
(8) Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.; Sambri, L. J .
Org. Chem. 1997, 62, 4183.
4
92077. Fax: +39 984 492055.
†
Universit a` della Calabria.
Dipartimento di Chimica Organica “A. Mangini”.
(9) Bartoli, G.; Cupone, G.; Dalpozzo, R.; De Nino, A.; Maiuolo, L.;
Marcantoni, E.; Procopio, A. Synlett 2001, 12, 1897. (b) Sabitha, G.;
Babu, R. S.; Rajkumar, M.; Srividya, R.; Yadav, J . S. Org. Lett. 2002,
3, 1149. (c) Cappa, A.; Marcantoni, E.; Torregiani, E.; Bartoli, G.;
Bellucci, M. C.; Bosco, M.; Sambri, L. J . Org. Chem. 1999, 64, 5696.
(10) Kobayashi, S.; Nagayama, S.; Busujima, T. J . Am. Chem. Soc.
1998, 120, 8287.
(11) Smith, P. H.; Reyes, Z. E.; Lee, C. W.; Raymond, K. N. Inorg.
Chem. 1988, 27, 4154.
(12) Chaundary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 95,
99.
‡
(
1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley and Sons: New York, 1999. (b)
Kocienski, P. J . Protecting Groups, 1st ed; George Thieme Verlag:
Stuttgart, 1994.
(
2) Kocienski, P. J . J . Chem. Soc., Perkin Trans. 1 2001, 2109-2135.
(3) Mark o´ , I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J . M.;
Quesnel, Y.; VAnherck, J . C. Angew. Chem., Int. Ed. 1999, 38, 3207.
b) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J . M.; Quesnel, Y.; Mark o´ ,
I. E. Tetrahedron Lett. 1999, 40, 1799.
(
(
(
(
4) Battacharjya, A.; Majumdar, S. J . Org. Chem. 1999, 64, 5682.
5) Yutaka, U.; Koumoto, N.; Fujisawa, T. Chem. Lett. 1989, 1623.
6) Steel, P. G. J . Chem. Soc., Perkin Trans. 1 2001, 2727. (b)
(13) Kanai, K.; Sakamoto, I.; Ogawa, S.; Suami, T. Bull. Chem. Soc.
J pn. 1987, 60, 1529.
(14) Adams, E.; Hiegermann, M.; Duddeck, H.; Welzel, P. Tetrahe-
dron 1990, 46, 5975.
(15) H o¨ fle, G.; Steglich, W.; Vorbr u¨ ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209.
7) Carrigan, M. D.; Sarapa, D.; Smith, R. C.; Wieland, L. C.; Mohan,
R. S. J . Org. Chem. 2002, 67, 1027.
(
1
0.1021/jo0260387 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002
J . Org. Chem. 2002, 67, 9093-9095
9093

TABLE 2. Clea va ge of Aceta ls a n d Keta ls in Wet CH 3NO2 Usin g Ce(OTf)3
a
After 24 h, the corresponding methyl ester (3.5%) and carboxylic acid were determined by GC-MS analysis. b After 4 days, the 1,2-
c
d
O-isopropylidene-D-glucopyranoside is still the only one product formed. Only a small percentage of TBDMS was cleaved. Prepared
according to literature methods.
according to literature methods.
1
2
e
13
f
14 g
Prepared according to literature methods.
Prepared according to literature methods.
Prepared
1
5
conditions for a long time. Any attempt to obtain dry
product failed, and in addition, the Ce(OTf) left at 110
C under vacuum gave a characteristic broad band of
saturated with water in the presence of cerium (III)
triflate (Table 2).
3
°
Except for cyclic acetals and ketals, which require a
-
1
water at 3300 cm on the IR spectrum.
We tested the catalytic activity of Ce(OTf)
3
0 mol % amount of catalyst, dialkyl acetals and ketals
3
in the
derived from aromatic (entries 4, 6, and 7, Table 2) as
well as aliphatic (entries 1, 2, and 5, Table 2) carbonyl
compounds underwent smooth deprotection at room
temperature using 5 mol % of catalyst only. No substan-
tial differences in reactivity between dimethyl and diethyl
ketals were registered.
deprotection of acetals and ketals at room temperature.
On the basis of our preliminary results, which are shown
in Table 1, for 2-phenyl-1,3-dioxolane, Ce(OTf)
efficiently in polar solvents such as CH NO
CN saturated with water. Less satisfactory results were
obtained in aqueous THF, and in CHCl saturated with
3
acts more
3
2
and CH -
3
3
When the dimethyl acetal of heptanal (entry 3, Table
water only 25% of deprotected product was collected. The
water seems to be an essential element in the reaction
pathway, and only very low yields of deprotected product
2
) was subjected to the reaction conditions, only 70% of
heptanal formed and even after longer reaction time (48
h) and more catalyst addition (30 mol %) only 79% of
heptanal was collected together with heptanoic acid and
its methyl ester (3.5% and 13.5%, respectively, based on
GC/MS analysis).
were obtained when dry CH
entry 5, Table 1). The molecular percent of catalyst is
also crucial and significantly lower yield of benzaldehyde
3 2
NO was used as solvent
(
was produced using only 15 mol % of Ce(OTf)
Table 1).
3
(entry 6,
Cyclic ketals were more resistant to the reagent than
the corresponding acetals (entries 8-11 and 12-15, Table
2), whereas the conjugated aliphatic cyclic acetals seems
to be easier to remove (entry 16, Table 2).
Based on the results reported in Table 1, we adopted
a simple experimental procedure that involves stirring
the solution of acetal or ketal substrates in CH
3 2
NO
9
094 J . Org. Chem., Vol. 67, No. 25, 2002

The cleavage of cyclic acetals and ketals of aromatic
carbonyl compounds was shown to be strongly dependent
on the presence of electron-withdrawing groups on the
aromatic ring. In fact, 2-(4-nitrophenyl)-1,3-dioxolane
gave only a low percentage in deprotection also after a
very long time and using a higher amount of catalyst
a weak acid (pH ) 6.7). The presence of water is
necessary to the reaction to proceed fully, and only low
yields of carbonyl compounds were obtained in dry CH
NO
3
-
2
.
In conclusion, we have described a new and chemose-
lective method for the cleavage of acetals and ketals at
room temperature in wet nitromethane under mild and
nearly neutral reaction conditions. The advantages of this
method are the general applicability in cleavage of alkyl
and cyclic acetals and ketals, the high yields of depro-
tected products, the observed selectivity, and a very
gentle reaction conditions such as the use of catalytic
amount of the reagent at room temperature and almost
neutral pH.
(entry 11, Table 2). No cleavage was registered for 2-(4-
nitrophenyl)-2-methyl-1,3-dioxolane under the same re-
action conditions (entry 15, Table 2).
Ce(OTf) was revealed to be a very useful tool for the
3
selective deprotection of isopropylidene ketals. Quantita-
tive yields of 1,2-isopropylidene-D-glucose were obtained
when the diacetone-D-glucose reacted with 30 mol % of
catalyst for 3 h (entry 17, Table 2); no other products were
recovered even after longer reaction time (48 h). Instead,
it was impossible to remove the more resistant ben-
zylidene acetal group from (4,6-O-benzylidene) methyl-
R-D-glucopyranoside (entry 18, Table 2), and even after
Exp er im en ta l Section
All the chemicals were purchased from commercial sources
besides the protected acetals 24-28, which were synthesized
according to trivial literature methods.
1
0 days, the starting material was recovered intact from
Typ ica l P r oced u r e. A solution of benzaldehyde dimethyl
the reaction mixture. Moreover, this method might be
used to selectively deprotect acetals in the presence of
several protecting groups (THP, Tr, Bn, p-MBn, TBDMS,
and TMDPS). Less than 5% of deprotected product was
recovered when alcohols protected with these groups were
subjected to the above-reported reaction conditions (en-
tries 19-23, Table 2). In fact, we were able to remove
chemoselectively the dimethyl acetal group in the pres-
ence of Ac, Bn, p-MBn, and TBDMS (entries 25-28,
Table 2).
acetal (152.2 mg, 1.0 mmol) and Ce(OTf)
mmol) in CH NO saturated with water (2.0 mL) was stirred at
room temperature. After 1 h, the CH NO was removed under
3
2
‚xH O (29.4 mg, 0.05
3
2
3
2
reduced pressure, and the residue was extracted with diethyl
ether. The organic layer was washed with a saturated brine
solution and dried over anhydrous sodium sulfate. Benzaldehyde
(
93%) was determined by GC-MS using the standard addition
method.
The solvent was removed on a rotary evaporator to yield 98.6
mg of benzaldehyde isolated by flash chromatography.
For all compounds reported in Table 2, full NMR and IR data
were compared with those of pure sample.
Several considerations can be studied in order to get
some mechanism insights. It is possible to rule out that
the triflic acid could be the active catalyst; in fact, a
Ack n ow led gm en t . We thank MIUR-Italy for the
financial assistance.
solution of Ce(OTf)
3
in water is only weakly acidic (pH
)
6.0), and the aqueous layer from the workup was also
J O0260387
J . Org. Chem, Vol. 67, No. 25, 2002 9095