Mild and chemoselective catalytic deprotection of ketals and acetals using cerium(IV) ammonium nitrate

Article abstract of DOI:10.1016/j.tet.2003.03.002

Cerium(IV) ammonium nitrate (CAN) is a powerful, though mild, reagent for the efficient and selective removal of a range of ketals and acetals. This novel deprotection method requires only catalytic amounts of CAN and tolerates a variety of functional and protecting groups. Mechanistic insights suggest that the Ce(IV) salts act as unique Lewis acids and not as redox active species.

Full text of DOI:10.1016/j.tet.2003.03.002

Tetrahedron 59 (2003) 8989–8999
Mild and chemoselective catalytic deprotection of ketals and
acetals using cerium(IV) ammonium nitrate
Ali Ates, Arnaud Gautier, Bernard Leroy, Jean-Marc Plancher, Yannick Quesnel,
*
´
´
Jean-Christophe Vanherck and Istvan E. Marko
´ ´ ˆ
Universite catholique de Louvain, Departement de Chimie, Batiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
Received 28 February 2003; accepted 4 March 2003
Abstract—Cerium(IV) ammonium nitrate (CAN) is a powerful, though mild, reagent for the efficient and selective removal of a range of
ketals and acetals. This novel deprotection method requires only catalytic amounts of CAN and tolerates a variety of functional and
protecting groups. Mechanistic insights suggest that the Ce(IV) salts act as unique Lewis acids and not as redox active species.
q 2003 Elsevier Ltd. All rights reserved.
The protection–deprotection sequence is probably the most
recurrent functional group interconversion in organic
synthesis.1 Amongst the numerous groups employed to
protect aldehydes and ketones, ketals and acetals occupy a
cardinal position.2 The plethora of ingenious methods
developed to append and subsequently remove them is a
clear testimony to their paramount importance.3
Figure 1.
Unfortunately, most of these procedures require rather harsh
acidic conditions, often incompatible with other sensitive
functions present in the substrate. Over the past few years,
milder protocols have emerged based upon the use of
catalytic amounts of Lewis acids or of non acidic reagents.4
In this context, we have recently described two original
procedures for the unveiling of ketals and acetals using
stoichiometric5 and catalytic6 amount of cerium(IV)
ammonium nitrate (CAN). In this Article, we wish to
describe our results in full and discuss in some details the
intimate mechanism of this reaction (Fig. 1).
4. A large variety of reagents, able to generate an alkoxy
radical from a hydroxyl function, have been reported in the
literature.8 Unfortunately, most of them proved unsuitable
to our purpose, affording poor yields of the desired ketone 5.
Attention was then focused on the use of cerium(IV)
ammonium nitrate, a reagent introduced by Trahanovski for
these kind of fragmentations9 and championed by Ho for
numerous other applications.10
Upon addition of 2.5 equiv. of CAN to a H2O/MeCN
solution of ketal 4, maintained at 708C, a deep red tinge
developed instantaneously.11 Within 2 min, it vanished
affording a colourless solution. At this stage, TLC
analysis indicated that the starting material 4 had been
completely consumed and that a single new product was
During the course of some synthetic studies directed
towards the preparation of natural products embodying a
medium ring system,7 we had the opportunity to examine
the radical-mediated fragmentation of the b-hydroxy-ketal
Figure 2.
Keywords: acetals; ketals; cerium and compounds; catalysis; deprotection.
*
Corresponding author. Tel. þ32-10-47-8773; fax: þ32-10-47-2788; e-mail: marko@chim.ucl.ac.be
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.03.002

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A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
formed. Unexpectedly, this compound proved to be the
b-hydroxy-ketone 6 rather than the anticipated fragmenta-
tion product 5 (Fig. 2).
Table 1. CAN-mediated deprotection of ketals and acetals
Entry Substrate Product
Yielda Time
(%)
(min)
Whilst CAN is well-reputed as a powerful oxidising agent
that can be used for the deprotection of S,S and O,S acetals
and ketals,12 for the cleavage of tert-butyldimethyl
silylethers13 and for the unravelling of tBOC groups,14 it
had not been employed, to the best of knowledge, to unmask
acetals and ketals. The surprisingly rapid and efficient
conversion of ketal 4 into the highly sensitive aldol product
6 spurred our interest and encouraged us to investigate in
greater detail the scope and limitations of this novel
deprotection protocol.
1
71
3
2
3
98
60
2
4
Thus, a range of substrates bearing representative functional
groups were prepared according to literature procedures and
reacted with CAN under the above-mentioned conditions.
Some pertinent results are collected in Table 1.
As can be seen from Table 1, a wide range of acetals and
ketals can be smoothly deprotected to the corresponding
aldehydes and ketones in good to excellent yields.15
Furthermore, the procedure tolerates a variety of functional
and protecting groups. For example, the presence of a
ketone or enone function in the same substrate is perfectly
compatible with the reaction conditions (Table 1, entries 1
and 2). The removal of the dioxolane moiety can also be
performed in the presence of an amide, a free alcohol, an
alkene and a benzyl ether (Table 1, entries 3–6).
Interestingly, the treatment of enone-derived ketals with
CAN leads in high yields to the regeneration of the desired
enones (Table 1, entry 7). Moreover, this reaction proceeds
equally efficiently with acyclic ketals and acetals (Table 1,
entries 8 and 9). It is noteworthy that over-oxidation of the
aldehyde product to the corresponding carboxylic acid was
not observed under these conditions. Finally, six-membered
ring ketals can be unravelled with equal ease and
competence as the corresponding five-membered analogues
(Table 1, entries 10 and 11). It is interesting to note that in
all cases, the removal of the dioxolane moiety occurs within
minutes, in stark contrast to the more classical acid-
catalysed protocols that usually require lengthy periods of
time. For example, whilst the treatment of ketal 15 (Table 1,
entry 5) with PTSA (20 mol%) in acetone necessitated 5
days to reach completion, quantitative conversion of 15 to
16 was accomplished in 3 min using the cerium(IV)-based
protocol. Although this novel, CAN-mediated, deprotection
technique appears to be broadly applicable, dimethylacetals
and TBS protecting groups are incompatible with this
procedure.16
4
5
79
77
2
3
6
7
97
84
2
5
8
83
4
9
70b
5
4
5
10
71
Despite the use of an excess of CAN and the requirement for
moderately high temperatures, the reaction conditions
appear to be sufficiently mild to tolerate some rather acid-
sensitive products (Fig. 3).
11
65
a
All yields refer to pure, homogeneous products. In all cases, the crude
yield of essentially pure product (.95%) is quantitative. The discrepancy
in yields is due to mechanical losses/volatily during the purification step.
Performed using a borate buffer (Merck, buffer pH¼8).
For example, attempted transformation of bicyclic ketal 28
into the corresponding ketone 29, using a variety of acid-
catalysed conditions, uniformly led to enone 30 in high
yields. In stark contrast, CAN-mediated removal of the
dioxolane protecting group afforded quantitatively the
desired b-hydroxy ketone 29. It is worthy to note that 29
b

A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
8991
Figure 3.
is exquisitely sensitive to acidic conditions and eliminates
water at the slightest incitement, generating enone 30.17
ketones and enones (Table 3, entries 4 and 5) and even
triisopropylsilyl (TIPS) ethers (Table 3, entry 6). It is
noteworthy that alcohols are not oxidised and that
aldehydes, stable under these conditions, do not form the
corresponding carboxylic acids (Table 3, entry 7). In sharp
contrast to the earlier protocol, employing stoichiometric
amounts of CAN, the epimerisation of acid-sensitive
substrates is suppressed with this catalytic variant (Table 3,
entry 8).19
Despite its synthetic interest, this protocol suffers from the
significant shortcoming that substantial quantities of CAN
(2.5 equiv. of a heavy and rather expensive complex) are
required, which precludes its transposition to large-scale
experiments. In order to remove this stringent limitation,
alternative procedures, employing catalytic quantities of
CAN in conjunction with stoichiometric amounts of an
inexpensive oxidant, were investigated. Examination of the
literature revealed that a variety of functional groups can be
oxidised using sub-stoichiometric quantities of CAN in the
presence of a range of co-oxidants.14 Among these methods,
the use of NaBrO3 attracted our attention18 and the
deprotection of the hydrindane derivative 31 was attempted
using 3 mol% of CAN and 1.5 equiv. of NaBrO3 (Table 2).
The surprising observation that CAN was not acting as an
oxidant in this process is further reinforced by the isolation,
in essentially quantitative yields, of the diol by-product 47,
generated during the unmasking of ketone 46 (Fig. 4).
This diol was not observed when the deprotection of ketal
45 was performed using stoichiometric amounts of CAN,
owing probably to its subsequent cleavage by the cerium
(IV) salts. The conditions of the catalytic CAN protocol are
sufficiently lenient to allow the selective unravelling of a
single dioxolane moiety in bis-protected ketals (Table 4).
Gratifyingly, the reaction proceeded smoothly and afforded
ketone 32 in 99% yield (Table 2, entry 1). Since the medium
proved to be acidic (vide infra), a borate buffer solution
(Merck, pH 8) was added in order to minimise eventual
side-reactions. Again, the desired product 32 was obtained
in high yield (Table 2, entry 2). The serendipitous omission
of the co-oxidant led to an unexpected observation.
Remarkably, even in the absence of NaBrO3, efficient
regeneration of ketone 32 from ketal 31 occurred,
suggesting that CAN was not acting as an oxidant but
rather as a specific Lewis acid (Table 2, entry 3). Some
pertinent examples, demonstrating the usefulness of this
novel protocol and the mildness of the reaction conditions
are collected in Table 3.
Under more forcing conditions, double deprotection can
also be achieved in excellent yield without interference with
the alcohol functions or the exo-cyclic double bond. Not
only dioxolanes but also a variety of other cyclic ketals can
be smoothly unveiled using this catalytic system (Fig. 5).
The complete inertness of the pinacol-derived substrate 57
suggests that the cerium catalyst is highly sentient to steric
hindrance in the ketal protecting group and/or in its
immediate vicinity. This sensitivity is further illustrated
by the prolonged reaction time required for the unmasking
of the decalone derivative 9 (Table 3, entry 5). It is
noteworthy that acidic treatment of 57 readily affords
tertbutyl-cyclohexanone 26 in high yields, highlighting
again the paramount role of the cerium salt in this process
and strongly suggesting the non-involvement of an acid-
catalysed manifold.
As can be seen from Table 3, a variety of ketals and acetals
can be smoothly deprotected using only catalytic quantities
of CAN (3 mol%) in the presence of a slightly basic buffer
and in the absence of a co-oxidant. This procedure tolerates
a wide range of functional groups, including unprotected
secondary and tertiary alcohols (Table 3, entries 2 and 3),
Table 2. Catalytic deprotection of ketal 31 with CAN
Entry
Conditions
3 mol% CAN/1.5 equiv. NaBrO3 MeCN/H2O (1/1), 708C
3 mol% CAN/1.5 equiv. NaBrO3 MeCN/borate buffer (pH 8), 708C
3 mol% CAN/borate buffer (pH 8) MeCN/H2O (1/1), 708C
Yielda (%)
1
2
3
99
90
93
a
All yields are for pure, isolated products.

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A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
Table 3. CAN-catalysed deprotection of acetals and ketals
Entry
1
Substrate
Product
Yielda (%)
Time
95
30 min
2
3
92
99
25 min
1.5 h
4
86b
1.5 h
5
6
7
95
91c
95
48 h
45 min
2.5 h
8
96c
20 min
a
All yields are for pure, isolated products.
Performed using 4 mol% CAN.
The reaction was carried out in the presence of 1.5 equiv. of NaBrO3.
b
c
To gain some insights into the mechanism of this novel
catalytic reaction, the deprotection of 25 was monitored
using cyclic voltamperometry (Fig. 6).
prepared as a blank and the spectrum was recorded (Fig. 6,
curve a). Then, cerium(IV) ammonium nitrate was added
and the spectrum, displaying the reduction and oxidation
potentials, was registered again. Under these conditions, and
using a sweep rate of 100 mV/s, CAN is reduced to the
At the onset, an acetonitrile–borate buffer solution was
Figure 4.

A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
8993
Table 4. Chemoselective CAN-catalysed deprotections of sugars
Yielda (%)
reduction peaks remained unaltered after the addition of
ketal 25, during the course of the reaction and at the end of
the deprotection (Figure 6, curve c). The only species
detected throughout the course of this reaction was Ce(IV),
clearly indicating that CAN does not behave as a redox
catalyst.
Entry
Substrate
Product
1
98
In order to discriminate between Brønstedt and Lewis acid
catalysis, a series of experiments were performed under
various pH conditions. Whilst it is difficult to ascertain with
precision the exact pH of an organic/water mixture, it
appears that a solution of CAN (3 mol%) in MeCN/H2O
(1/1) is rather acidic (pH,1.8). However, several experi-
ments have already hinted at the dearth of Brønstedt acid
participation, including the inertness of the pinacol-derived
ketal 57 (Fig. 5), the absence of epimerisation in the
unravelling of substrate 43, particularly rapid under acid-
catalysed conditions (Table 3, entry 8), and the lack of
fragmentation during the generation of diketone 38, a
process that occurs readily in the presence of various acids
(Table 3, entry 4).20
2
81
3
97
a
All yields are pure, isolated products.
Nonetheless, some buffered solutions of nitric acid and
CAN were prepared (pH¼1.8–4.4) and the deprotection of
ketal 21 was performed at different pH and monitored by
GC (Fig. 7).
At low pH, the rate of disappearance of 21 and the velocity
of formation of 22 proved to be virtually identical using
either CAN or HNO3, thus thwarting our efforts to
distinguish between the two possible competing manifolds.
However, whilst reaction of 21 with 3 mol% CAN (buffered
at pH 4.4 with pyridine) led to almost complete formation of
22 after 1 h (Fig. 7, Chromatogram 1) and quantitative
unveiling of 21 after 3 h (Fig. 7, Chromatogram 2), less than
20% of ketone 22 was produced when a pyridine/HNO3
solution (pH¼4.4) was employed (Fig. 7, Chromatogram 3).
This result clearly establishes that the cerium(IV) salts are
the active catalytic species in this unique, mild deprotection
Figure 5.
Ce(III) state at a potential of 2485.7 mV and is reoxidised
to Ce(IV) at 2357.2 mV vs SCE (Fig. 6, curve b). The
shape of the curve and the positions of the oxidation and
Figure 6.

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A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
Figure 7.
Figure 8.
methodology.21 Finally, the tolerance of this system towards
acid-sensitive functions is further illustrated by the
competition experiment displayed in Figure 8.
preferred choice when acid-labile functions had to be
preserved.
Thus, treatment of an equimolar mixture of THP ether 58
and trityl protected alcohol 59 with 3 mol% CAN in MeCN/
borate buffer, at 608C, smoothly afforded 60 and recovered
59 in essentially quantitative yields. The inertness of the
trityl protecting group, usually highly labile towards acids,
under the CAN-catalysed conditions stands as a clear
testimony to the lack of involvement of Brønstedt acids in
this protocol. The steric bulk of the trityl group efficiently
shields the ether oxygen from the cerium reagent and
inhibits its deprotection.
1. Experimental
Most of the commercially available reagents were used
without further purification. Methylene chloride and
acetonitrile were distilled over calcium hydride. Diethyl-
ether and THF were distilled over sodium and benzo-
phenone. Whenever required, the glassware was flame dried
prior to use and the reactions were carried out under an
argon atmosphere. NMR spectra were recorded on Varian
Gemini 200 and 300 MHz FT-NMR spectrometers. IR
spectra were recorded on a Bio-Rad FTS FT-IR spec-
trometer. Mass analyses were performed in the mass
spectroscopy laboratory of the Universite catholique de
Louvain on VARIAN Matt 44S or Finnigan-Matt TSQ-70
spectrometers. Elemental analyses were performed at the
¨
Institut fu¨r Organishe Chemie, Universitat Stuttgart,
Germany. High resolution mass spectra were obtained
from the laboratory of mass spectrometry of the Universite
de Mons-Hainaut, Belgium. Thin-layer chromatography
was carried out on aluminium-supported plates and stained
by potassium permanganate or UV light. Purifications by
column chromatography were performed on Merck 60 silica
gel (0,040–0,063 mm). Fused silica capillary column,
Chrompack, CP-Sil 8 CB, 30 m£0.25 mm, 0.25 m. Program
used: initial temperature (508C), rate (108/min), final
temperature (2908C). Voltammetry performed using a
potentiostat/galvanostat from Princeton Applied Research
(software M270) with a scanning rate of 100 mV/s.
In summary, we have shown that cerium(IV) ammonium
nitrate is a powerful reagent for the efficient and selective
unravelling of a variety of ketal and acetal protecting
groups. The conditions are mild, employ a catalytic amount
of the cerium reagent and tolerate a wide range of
functionalities, including unprotected alcohols, ketones,
aldehydes, enones and even trityl ethers.22 The mechanism
of the stoichiometric CAN-mediated deprotection seems to
proceed via a sequence of single electron-transfer—as
suggested by the appearance of a transient deep-red
colour11—whilst the catalytic CAN protocol appears to
involve the participation of Ce(IV) salts which act as highly
selective Lewis acids and not as redox active species (no
deep-red colour was observed in these cases). Finally, we
have demonstrated that Brønstedt acid catalysis did not play
a significant role in the mechanism of this unique procedure
and that the use of CAN/pyridine (pH¼4.4) was the
´
´

A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
8995
1.1. Stoichiometric CAN mediated deprotections (typical
procedure)
pure (79%). IR (neat) 3401, 2932, 2668, 1696, 1459, 1443,
1244, 1144, 971 cm21; 1H NMR (500 MHz, CDCl3) d 0.95
(3H, d, J¼7.1 Hz), 1.24 (1H, dddd, J¼12.5, 12.5, 12.0,
3.5 Hz), 1.32 (1H, ddddd, J¼12.5, 12.5, 12.5, 3.6, 3.6 Hz),
1.46 (1H, dqd, J¼12.0, 7.1, 3.5 Hz), 1.56–167 (3H, m),
1.68–1.93 (5H, m), 2.02 (1H, ddddd, J¼13.4, 13.4, 13.4,
4.4, 4.4 Hz), 2.12–2.17 (1H, m), 2.18–2.25 (1H, m), 2.43
(1H, ddd, J¼14.5, 13.4, 7.0 Hz); 13C NMR (75 MHz,
CDCl3) d 14.4, 20.3, 23.2, 25.2, 29.3, 31.7, 37.0, 43.1, 61.7,
77.3, 215.6; MS (70 eV) m/z (Mþz) 182 (80%), 167 (6%),
164 (28%), 154 (20%), 139 (78%), 126 (100%), 55 (60%),
43 (42%), 41 (38%); Anal. calcd for C11H18O2: C, 72.72%;
H, 10.07%. Found: C, 72.49%; H, 9.95%.
To a stirred solution (60–708C) of the substrate (1 mmol),
dissolved in acetonitrile (3 ml), was added in one portion, a
solution of CAN (1.36 g, 2.5 mmol) in water (3 ml). The
resulting mixture became instantaneously red-brown and
the colour discharged after the required amount of time
(Table 1) to give a slightly yellow solution. After extraction
with ether or dichloromethane (3£10 ml), the combined
organic layers were dried over MgSO4, filtered and the
solvents were removed in vacuo. The crude product was
purified, if required, by silica-gel column chromatography.
Crude compound 8 was .95% pure (colourless oil, 71%),
data identical to an authentic commercial sample, (RN [106-
51-4], Aldrich). Crude compound 1823 was .95% pure
(97%), data identical to an authentic sample, (RN [2987-06-
6]). Crude compound 20 was purified by bulb-to-bulb
distillation (608C, 20 mm Hg; colourless oil, 84%), data
identical to an authentic commercial sample, (RN [930-30-
3], Fluka). Crude compound 22 was .95% pure (83%), data
identical to an authentic commercial sample, (RN [112-12-
9], Fluka). Crude compound 24 was purified by silica-gel
column chromatography (dichloromethane/petroleum ether
1/1; colourless oil, 70%), data identical to an authentic
commercial sample, (RN [104-53-0], Fluka). Crude com-
pound 26 was .95% pure (71% starting from compound 25
and 65% starting from compound 27), data identical to an
authentic commercial sample, (RN [98-53-3], Aldrich).
1.1.5. (4aRp,8Sp,8aSp)-8-(3-Butenyl)-4a-hydroxyocta-
hydro-1(2H)-naphthone (16). Crude compound 16 was
.95% pure (77%). IR (neat) 3419, 3075, 2930, 2867, 1702,
1
1641, 1450, 1353, 1315, 1262 cm21;; H NMR (500 MHz,
CDCl3) d 0.88 (1H, dddd, J¼13.5, 13.5, 13.5, 4.1 Hz), 1.15
(1H, dddd, J¼14.5, 9.4, 9.4, 5.1 Hz), 1.28 (1H, dddd,
J¼14.5, 9.6, 7.2, 3.3 Hz), 1.37 (1H, ddd, J¼13.5, 13.5,
4.1 Hz), 1.42–1.47 (1H, m), 1.49 (1H, ddddd, J¼13.5, 13.5,
13.5, 3.5, 3.5 Hz), 1.63 (1H, s), 1.71–1.81 (2H, m), 1.84
(1H, dddd, J¼13.5, 3.5, 3.15, 1.1 Hz), 1.87–1.98 (4H, m),
2.10 (1H, ddddd, J¼13.5, 13.5, 13.5, 4.2, 4.2 Hz), 2.13 (1H,
m), 2.19 (1H, ddd, J¼13.5, 13.5, 4.1 Hz), 2.22 (1H, m), 2.35
(1H, ddd, J¼13.5, 13.5, 4.1 Hz), 4.90–5.05 (2H, m), 5.70
(1H, dddd, J¼17, 10, 7.3, 6.3 Hz); 13C NMR (75 MHz,
CDCl3) d 21.5, 22.7, 30.2, 30.3, 32.6, 37.6, 37.7, 40.5, 66.7,
76.2, 114.8, 138.2, 215.0; MS (70 eV) m/z (Mþz) 222 (31%),
205 (25%), 204 (30%), 194 (12%), 162 (38%), 149 (80%),
113 (95%), 55 (100%), 41 (77%); Anal. calcd for C14H22O2:
C, 75.65%; H, 9.94%. Found: C, 75.63%; H, 9.97%.
1.1.1. 4a-Hydroxy-octahydro-naphthalen-1-one (6). The
crude mixture was purified by column chromatography over
silica-gel (petroleum ether/ethyl acetate 2/1) to give 6 as a
colourless oil (78%). IR (neat) 3437, 2934, 2864, 1707,
p
p
´
1.1.6. (4aR ,9aR )-4a-Hydroxydecahydro-1H-benzo
[a]cycloheptan-1-one (29). The crude product was purified
by column chromatography over silica-gel (petroleum ether/
ethyl acetate 3/1) to give 29 as a white solid (96%). Mp 77–
788C. IR (neat) 3460, 2918, 2853, 1696, 1450, 1390, 1296,
1177, 1003, 945, 827 cm21; 1H NMR (500 MHz, CDCl3) d
1.18–1.28 (1H, m), 1.35–1.53 (3H, m), 1.64–1.79 (4H, m),
1.84–1.97 (4H, m), 2.05–2.16 (2H, m), 2.27 (1H, ddd,
J¼13.2, 13.2, 6.6 Hz), 2.34–2.40 (1H, m), 2.42 (1H, d,
J¼10.0 Hz); 13C NMR (125 MHz, CDCl3) d 20.1, 21.4,
21.7, 26.9, 28.5, 39.1, 40.4, 43.7, 60.5, 78.6, 211.5; MS
(70 eV) m/z (Mþz) 182 (100%), 164 (22%), 154 (45%), 139
(66%), 126 (43%), 122 (41%), 111 (37%); Anal. calcd for
C11H18O2: C, 72.49%; H, 9.95%. Found: C, 71.97%; H,
9.83%.
1
1450, 1353, 1141 cm21; H NMR (300 MHz, CDCl3) d
1.14–1.92 (9H, m), 1.93–2.52 (6H, m); 13C NMR (75 MHz,
CDCl3) d 20.5, 22.6, 23.7, 25.6, 33.7, 38.2, 38.3, 59.1, 74.6,
212.7; MS (EI, 70 eV) m/z (Mþz) 168.1 (100%), 150 (50%),
140 (10%), 139.2 (20%), 125.1 (26%), 113 (30%), 55
(12%); Anal. calcd for C10H16O2: C, 71.39%; H, 9.59%.
Found: C, 70.93%; H, 9.70%.
1.1.2. 5,8a-Dimethyl-3,4,8,8a-tetrahydro-2H,7H-
naphthalen-1,6-dione (10). Crude compound 10 was
.95% pure (colourless oil, 98%); 1H NMR (300 MHz,
CDCl3) d 1.43 (3H, s), 1.66–1.87 (4H, m), 2.01–2.24 (3H,
m), 2.37–2.60 (4H, m), 2.69 (1H, ddd, J¼15.9, 10.5,
6.0 Hz), 2.9 (1H, dtd, J¼15.9, 5.0, 1.2 Hz); 13C NMR
(75 MHz, CDCl3) d 11.1, 21.3, 23.2, 27.2, 29.6, 33.2, 37.2,
50.6, 130.7, 158.3, 197.6, 211.9; RN [41019-71-0].
1.1.7. 2,3,4,5,6,7,8,9,-Octahydro-1H-benzo[a]cyclo-
hepten-1-one (30).24 To a stirred solution of substrate 28
(100 mg, 0.44 mmol) dissolved in acetone (5 ml) was added
in one portion, solid PTSA (10 mg, 5% wt). The resulting
mixture was refluxed 15 h and then cooled to room
temperature. Solid NaHCO3 (35 mg) was added and the
solvent was removed in vacuo. Water (15 ml) was then
added and the aqueous phase was extracted with dichloro-
methane (3£20 ml). The organic extracts were dried over
MgSO4, filtered and the solvent was removed in vacuo to
afford 30 as a colourless oil (71.6 mg, 99%). IR (neat) 2921,
2850, 1662, 1629, 1450, 1378, 1323, 1292, 1187,
1.1.3. 1-Acetyl-piperidin-4-one (12). Crude compound 12
was .95% pure (60%). IR (neat) 2967, 2883, 1717, 1649,
1
1429.3, 1237 cm21; H NMR (200 MHz, CDCl3) d 2.20
(3H, s), 2.48 (2H, t, J¼6.1 Hz), 2.51 (2H, t, J¼6.1 Hz), 3.73
(2H, t, J¼6.6 Hz), 3.89 (2H, t, J¼6.3 Hz); 13C NMR
(75 MHz, CDCl3) d 206.6, 169.3, 44.7, 40.9, 40.5, 40.4,
21.2; MS (70 eV) m/z (Mzþ) 141 (100), 113 (45), 98 (23);
RN [32161-06-1].
1.1.4. (4aSp,5Rp,8aSp)-4a-Hydroxy-5-methyloctahydro-
1(2H)-naphthone (14). Crude compound 14 was .95%
1103 cm21; 1H NMR (300 MHz, CDCl3) d 1.40 (2H,
;

8996
A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
quint J¼5.1 Hz), 1.55 (2H, quint J¼4.8 Hz), 1.77 (2H,
quint, J¼5.5 Hz), 1.93 (2H, quint, J¼6.0 Hz), 2.30–2.58
(8H, m); 13C NMR (75 MHz, CDCl3) d 22.3, 23.7, 25.2,
26.1, 32.0, 33.2, 36.6, 37.0, 138.0, 162.9, 198.2; MS (70 eV)
m/z (Mþz) 164 (100%), 149 (81%), 136 (65%), 121 (16%),
108 (38%), 93 (55%).
The faint yellow solution was heated at 608C during 1.5 h.
After cooling to room temperature, H2O (10 ml) was added.
The organic layer was separated and the aqueous phase
was extracted with dichloromethane (2£15 ml). The
combined organic extracts were dried over MgSO4,
filtered and the solvents were removed in vacuo. The
crude mixture was purified by column chromatography
over silica gel (ethyl acetate/hexane 3/7) to give Spiro[5,4]-
decane-2,7-dione 38 as a colourless liquid (144 mg,
1.2. Catalytic CAN mediated deprotections (typical
procedure)
1
86%). IR (neat) 1734, 1700 cm21; H NMR (300 MHz,
To a stirred solution of substrate (1 mmol) dissolved in
acetonitrile (3 ml) was added a borate buffer (Merck, pH 8,
3 ml). The mixture was heated at 60–708C and solid CAN
(16 mg, 3 mol%) was added. The resulting slightly yellow
solution was stirred for the required amount of time
(Table 2) at this temperature. After cooling to room
temperature, the reaction mixture was extracted with ether
(3£10 ml). The combined organic layers were dried over
MgSO4 filtered and the solvents were removed in vacuo.
The crude product was purified, if required, by silica-gel
column chromatography.
CDCl3) d 2.7 (2H, m), 2.42 (1H, dt, J¼14.1, 5.1 Hz),
2.31 (2H, dt, J¼8, 1.7 Hz), 2.2–1.6 (9H, m); 13C NMR
(75 MHz, CDCl3) d 18.9, 21.0, 26.6, 33.7, 35.9, 38.4, 39.7,
64.3, 207.9, 215.5; MS (70 eV) m/z (Mþz) 166 (92), 167
(100).
1.2.3. 3-(6-Hexyl-tetrahydro-pyran-2-yl)-propionalde-
hyde (42). The crude mixture was purified by column
chromatography over silica-gel (dichloromethane) to give
42 as a colourless oil (95%); 1H NMR (300 MHz, CDCl3) d
9.72 (1H, t, J¼1.7 Hz), 3.10–3.26 (2H, m), 2.38–2.60 (2H,
m), 1.64–1.83 (3H, m), 0.98–1.55 (15H, m), 0.83 (3H, t,
J¼6.51 Hz); 13C NMR (75 MHz, CDCl3) d 202.7, 77.9,
76.6, 40.4, 36.5, 31.8, 31.7, 31.6, 29.3, 29.0, 25.5, 23.6,
22.6, 14.0.
Crude compound 36 was purified by column chromato-
graphy over silica-gel (ethyl acetate/ether 4/1; colourless
oil, 92%), data identical to an authentic sample, (RN
[13482-22-9]). Crude compound 6 was .95% pure (99%),
see above for analysis. Crude compound 10 was .95% pure
(99%), see above for analysis. Crude compound 60 was
.95% pure (95%), data identical to an authentic com-
mercial sample, (RN [100-51-6], Acros).
1.2.4. 2-Allyl-4-tert-butyl-cyclohexanone (44) (trans/cis
96/4). To a stirred solution of 43 (238 mg, 1 mmol)
dissolved in acetonitrile (3 ml) was added water (3 ml)
and sodium bromate (226 mg, 1.5 mmol). The mixture was
then heated at 708C and solid CAN (16.5 mg, 3 mol%) was
added. The resulting slightly yellow solution was stirred
20 min at this temperature. After cooling to room tempera-
ture, the reaction mixture was extracted with dichloro-
methane (3£10 ml) and the combined organic layers were
dried over MgSO4, filtered and the solvents were removed
in vacuo to afford 44 as a colourless oil. Crude compound 44
was .95% pure (186 mg, 96%). (trans) RN [15781-18-7];
1H NMR (300 MHz, CDCl3) d 5.78–5.62 1H, m), 5.10–
5.02 (2H, m), 2.52–1.01 (10H, m), 0.89 (9H, s). 13C NMR
(75 MHz, CDCl3) d 201.9, 135.5, 116.9, 48.5, 41.1, 38.6,
35.5, 32.4, 30.3, 27.4, 26.6; cis) RN [15781-11-0]; 1H NMR
(300 MHz, CDCl3) d 5.88–5.71 (1H, m), 5.02–4.98 (2H,
m), 2.59–1.02 (10H, m), 0.91 (9H, s); 13C NMR (75 MHz,
CDCl3) d 201.1, 136.6, 116.1, 49.1, 47.0, 41.6, 33.7, 32.5,
28.7, 27.7, 27.6.
1.2.1. (3aSp,7aRp)-7a-Hydroxyoctahydro-4H-inden-4-
one (32).25 To
a stirred solution of 31 (200 mg,
1.01 mmol) dissolved in acetonitrile (4 ml) was added
water (4 ml) and sodium bromate (228 mg, 1.51 mmol). The
mixture was heated at 708C and solid CAN (16 mg, 3 mol%)
was added. The resulting, slightly yellow solution was
stirred 20 min at this temperature. After cooling to room
temperature, the reaction mixture was extracted with
dichloromethane (3£10 ml). The combined organic layers
were dried over MgSO4, filtered and the solvent was
removed in vacuo to afford 32 as a colourless oil (155 mg,
99%). Using the same procedure, but adding a borate buffer
(pH 8) instead of water, compound 32 was isolated in 90%
yield. Using the same procedure, but adding a borate buffer
(pH 8) instead of water and omitting sodium bromate,
compound 32 was isolated in 93% yield. Colourless oil. IR
(neat) 3423, 2959, 2875, 1699, 1458, 1345, 1311, 1157,
1079, 987 cm21; 1H NMR (300 MHz, CDCl3) d 1.52–2.28
(10H, m), 2.29–2.49 (2H, m), 2.51–2.74 (2H, m); 13C NMR
(75 MHz, CDCl3) d 21.0, 21.3, 24.5, 34.7, 38.0, 39.3, 60.8,
84.3, 211.6; MS (70 eV) m/z (Mþz) 154 (100%), 139 (78%),
137 (81%), 136 (93%), 126 (82%), 125 (61%), 113 (63%),
111 (90%), 108 (95%), 97 (64%), 94 (70%), 84 (82%), 70
(63%), 55 (96%), 42 (83%). This compound could not be
purified by silica-gel column chromatography due to its
rapid transformation into the corresponding enone.
1.2.5. Cyclohexanone (46) and 1,2-octanediol (47). To a
stirred solution of 19 (200 mg, 0.88 mmol) dissolved in
acetonitrile (4 ml) was added water (4 ml) and sodium
bromate (290 mg, 1.33 mmol). The mixture was then heated
at 808C and solid CAN (14 mg, 3 mol%) was added. The
resulting slightly yellow solution was stirred 20 min at this
temperature. After cooling to room temperature, the
reaction mixture was extracted with ether (3£10 ml). The
organic layers were dried over MgSO4, filtered and the
solvents removed in vacuo to afford 225 mg of a crude oil.
The crude product was further purified by column
chromatography over silica-gel (ethyl acetate/petroleum
ether 1/2) to give 46 as a colourless oil (81 mg, 95%) and 47
as a white solid (124 mg, 97%). Data identical to the
authentic commercial samples (46, RN [108-94-1]; 47, RN
[1117-86-8], Acros).
1.2.2. Spiro[5,4]decan-2,7-dione (38).26 Solid cerium
ammonium nitrate (CAN, 18 mg, 4 mol%) was added at
room temperature to a stirred solution of 2-oxo-7-dioxo-
lano-bicyclo [5,4,1] octane (237 mg, 1.13 mmol) dissolved
in MeCN (3.5 ml)/Borate buffer (3.5 ml, Merck, pH¼8).

A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
8997
1.2.6. 1,2-O-Isopropylidene-a-D-xylofuranose (49).27 To
1.4. 4-tert-Butyl-cyclohexanone (26) (voltammetry
experiment)
a stirred solution of 1,2-3,4 diisopropylidene xylose 48
(66 g, 0.287 mol) dissolved in water (265 ml) and aceto-
nitrile (250 ml) was added solid CAN (4.7 g, 8.6 mmol,
3 mol%). The resulting solution was stirred 18 h at room
temperature. After that, NH4OH (28%, 20 ml) was added
and the resulting yellow-orange suspension was filtered over
Celigel (celite/silica-gel: 9/1 w/w) and washed with MeOH
(150 ml). The solvents were removed in vacuo and the
residue dried overnight at room temperature to afford 49 as a
pale yellow oil (53.4 g, 98%); 1H NMR (200 MHz, CDCl3)
d 5.91 (1H, d, J¼3.7 Hz), 4.46 (1H, d, J¼3.7 Hz), 4.24 (1H,
d, J¼3.0 Hz), 4.11 (1H, q, J¼3.0 Hz), 3.96 (2H, t,
J¼4.0 Hz), 1.42 (3H, s), 1.25 (3H, s); 13C NMR (50 MHz,
CDCl3) d 111.4, 104.5, 85.1, 79.8, 75.2, 60.1, 26.4, 25.9.
Data identical to an authentic, commercial sample, (49, RN
[20031-21-4], Aldrich).
To a stirred solution of acetonitrile (30 ml) and borate buffer
(Merck, pH 8, 30 ml) was added CAN (164 mg, 3 mol%)
followed by potassium nitrate (6.1 g, 60 mmol) as the
electrolyte. A cyclic voltammetry of this solution was
recorded. After that, substrate 27 was added (2 g, 10 mmol).
The resulting mixture was then stirred 20 min at room
temperature. Complete deprotection of compound 27 had
occurred during that time (GC analysis) and a cyclic
voltammogram was recorded under the same conditions as
described above. The two curves were shown to be
identical; only cerium(IV) species were detected.
Acknowledgements
1.2.7. 1,2-O-Isopropylidene-a-D-glucofuranose (51). To a
stirred solution of diacetone-D-glucose 50 (1 g, 3.8 mmol)
dissolved in water (2 ml) and acetonitrile (10 ml) was added
solid CAN (21 mg, 0.038 mmol, 1.5 mol%). The resulting
solution was stirred 2 days at room temperature. After that,
NH4OH (28%, 1 ml) was added and the resulting suspension
was filtered over Celigel (celite/silica-gel: 9/1 w/w) and
washed with MeOH (10 ml). The solvents were removed in
vacuo and the residue dried using an azeotropic-toluene
distillation to afford 51 as a white powder (812 mg, 81%);
1H NMR (200 MHz, CD3OD) d 5.75 (1H, d, J¼3.6 Hz),
4.36 (1H, d, J¼3.6 Hz), 4.09 (1H, d, J¼2.6 Hz), 3.90 (1H,
dd, J¼2.6, 8.4 Hz), 3.65 (2H, m), 3.45 (1H, dd, J¼5.9,
11.7 Hz), 1.33 (3H, s), 1.18 (3H, s); 13C NMR (50 MHz,
CD3OD) d 114.3, 107.9, 88.0, 82.8, 77.0, 71.9, 66.7, 28.6,
28.0. Data identical to an authentic, commercial sample,
(51, RN [18549-40-1], Aldrich).
Financial support of this work was generously provided by
´
the Universite catholique de Louvain, Merck, the Actions de
recherche concertees (convention 96/01-197) and the Fond
´
National de la Recherche Scientifique (Dossier N8
2.4571.98). I. E. M. is thankful to the Fond pour la
`
Formation a la Recherche dans l’Industrie et dans
l’Agriculture (FRIA) for providing studentships to B. L.,
A. A. and J. C. V. Rhodia and Zeneca are gratefully
acknowledged for offering postdoctoral fellowships to A. G.
and Y. Q. respectively. We are also indebted to Professor
P. Claes and Mrs A. Masure for kindly performing the
cyclic voltamperometric experiments. Finally, I. E. M. is
appreciative to Merck for receiving the Merck Academic
Development Award and to Rhodia for the 2001 Rhodia
Outstanding Award.
1.2.8. a-D-Ribo-hexofuranose, 3-deoxy-3-methylene-1,2-
O-isopropylidene (53).28 To a stirred solution of a-D-ribo-
hexofuranose, 3-deoxy-3-methylene-1,2-4,5-O-diisopropyl-
idene 52 (3 g, 11.7 mmol) dissolved in water (30 ml) and
acetonitrile (30 ml) was added solid CAN (192 mg,
0.35 mmol, 3 mol%). The resulting solution was stirred
24 h at room temperature. After that, NH4OH (28%, 5 ml)
was added and the resulting suspension was filtered over
Celigel (celite/silica-gel: 9/1 w/w) and washed with MeOH
(50 ml). The solvents were removed in vacuo and the
residue dried overnight at room temperature to afford 53 as a
colourless oil (2.05 g, 97%). Data identical to the reported
spectroscopic values.
References
1. For beautiful illustrations of the skillful use of protecting
groups in organic synthesis, see: Nicolaou, K. C.; Sorensen,
E. J. Classics in Total Synthesis; VCH: Weinheim, 1996.
2. (a) Kocienski, P. J. Protecting Groups; Georg Thieme: New
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3. For some selected references, see: (a) Ballou, C. E.; Fischer,
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1.3. Preparation of CAN and nitric acid solutions for
catalytic experiments
CAN in water (pH 1.6), to a stirred water solution (19 ml)
was added CAN (105 mg, 0.19 mmol). CAN in borate
buffer (pH 1.8), to a stirred borate buffer solution (Merck,
pH 8, 19 ml) was added CAN (105 mg, 0.19 mmol). CAN in
water/pyridine (pH 4.4), to a stirred water solution (19 ml)
was added CAN (105 mg, 0.19 mmol) and pyridine (60 ml,
0.76 mmol). Nitric acid in water (pH 4.4), to a stirred
water solution (19 ml) was added dropwise a concentrated
nitric acid solution (14 M) until a pH value of 4.4 was
reached.
4. For some pertinent references, see: (a) Dalpozzo, R.; De Nino,
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A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
(d) Heravi, M. M.; Tajbakhsh, M.; Habibzadeh, S.;
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Ghassemzadeh, M. Monatsh. Fur Chem. 2001, 132, 985.
(e) Ko, K.-Y.; Park, S.-T.; Choi, M.-J. Bull. Korean Chem.
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15. The discrepancy between the yields of the crude products and
the pure samples mostly reflects the mechanical losses
encountered during the purification step (volatility) or the
instability of the compounds towards the support used for the
chromatography. In general, the crude products are sufficiently
pure (.95% purity) to be used as such in a subsequent
transformation.
5. Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.;
´
Marko, I. E. Tetrahedron Lett. 1999, 40, 1799.
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6. (a) Marko, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher,
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16. In the case of dimethylacetals, the competitive formation of
the corresponding methyl esters has been observed. For
sometime, we have not been able to define suitable reaction
conditions under which unmasking of a dioxolane function
could be accomplished chemoselectively in the presence of a
TBS protecting group. Recently, we and others have shown
that in some cases, such selective deprotections could be
´
Engl. 1999, 38, 3207. (b) Marko, I. E.; Ates, A.; Gautier, A.;
Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C.
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7. Marko, I. E.; Ates, A. Synlett 1999, 1033.
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´
accomplished using CAN/Py (pH 4.4). (a) Ates, A.; Marko,
I. E. Unpublished results. (b) Barone, G.; Bedini, E.; Iadonisi,
A.; Manzo, E.; Parrilli, M. Synlett 2002, 1645. For the removal
of ketals using CeCl3, see: (c) Marcantoni, E.; Nobili, F.;
Bartoli, G.; Bosco, M.; Sambri, L. J. Org. Chem. 1997, 62,
4183. For the selective CAN-mediated deprotection of TBS
ethers in the presence of ketals, in MeOH/water, see Ref. 13.
17. For example, attempted purification of hydroxyketone 29 by
silica gel column chromatography resulted in its rapid
transformation into enone 30.
9. Trahanovsky, W. S.; Young, M. G.; Nave, P. M. Tetrahedron
Lett. 1969, 10, 2501.
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Organic Synthesis by Oxidation with Metal Compounds; Mijs,
W. J., deJonge, C. R. H. I., Eds.; Plenum: New York, 1986.
11. The deep colour that develops during these reactions is
probably due to some charge–transfer complexes between
CAN and the ketal protecting group. A solution of CAN in
water or in water/MeCN is slightly yellow-coloured. For the
formation of red-tinged complexes between CAN and
alcohols, see: (a) Littler, J.-S.; Waters, W. A. J. Chem. Soc.
1960, 2767. (b) Young, L. B.; Trahanovsky, W. S. J. Am.
Chem. Soc. 1969, 91, 5060. For electron-transfer reactions
involving CAN, see: (c) Baciocchi, E.; Giacco, T. D.; Rol, C.;
Sebastiani, G. V. Tetrahedron Lett. 1989, 30, 3573. A
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Figure 9.
18. (a) Ho, T. L. Synthesis 1978, 936. (b) Olah, G. A.; Gupta, B. G.
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19. Using 2.5 equiv. of CAN or a variety of acid catalysts,
complete epimerisation of 44 occurs, affording a near
thermodynamic mixture of axial and equatorial product in a
ratio of 60/40. This experiment is a clear testimony to the
lenient reaction conditions prevailing in our catalytic
procedure.
20. Under acidic conditions, a competitive fragmentation of the
spiro bicyclic system has been observed, leading to
the corresponding cyclohexanone derivative bearing at the
a-position a 20-hydroxyethyl-4-butanoic ester side chain.
21. The CAN/py (pH 4.4) system has been discovered in this
laboratory by Dr Ali Ates during the mechanistic study of the
CAN-catalysed deprotection of 21. These results have been
communicated in all good faith to Dr Manzo, E. (visiting
scientist) and Professor Parrilli, M. who subsequently
published them Manzo, E.; Barone, G.; Bedini, E.; Iadonisi,
A.; Mangoni, L.; Parrilli, M. Tetrahedron 2002, 58, 129. and
Ref. 16b.
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Tetrahedron Lett. 1996, 37, 2035. For other deprotections
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Tetrahedron Lett. 1989, 30, 433. (c) Matsumoto, T.; Katsuki,
M.; Jona, H.; Suzuki, K. J. Am. Chem. Soc. 1991, 113, 6982.
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(e) Nair, V.; Nair, L. G.; Balagopal, L.; Rajan, R. Indian
22. For the selective cleavage of trityl ethers, see: (a) Yadav, J. S.;
Reddy, B. V. S. Synlett 2000, 1275. (b) Yadav, J. S.; Reddy,
B. V. S. Carbohydr. Res. 2000, 329, 885. (c) Lu, R. J.; Liu, D.;
Giese, R. W. Tetrahedron Lett. 2000, 41, 2817. For the
Figure 9.

A. Ates et al. / Tetrahedron 59 (2003) 8989–8999
8999
selective deprotection of ketals in the presence of trityl ethers,
´
see: (d) Marko, I. E.; Ates, A.; Augustyns, B.; Gautier, A.;
25. Kopecky, K. R.; Lockwood, P. A.; Gomez, R. R.; Ding, J.-Y.
Can. J. Chem. 1981, 59, 851.
26. Williams, J. R.; Sarkisian, G. M. J. Org. Chem. 1972, 37,
4463.
´ ´ ´ ´
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5613. (e) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Srividya, R.;
Yadav, J. S. Org. Lett. 2001, 3, 1119. (f) Xiao, X.; Bai, D.
Synlett 2001, 535.
L. Carbohydr. Res. 1998, 308, 297.
28. (a) Brimacombe, J. S.; Miller, J. A.; Zakir, U. Carbohydr. Res.
1976, 49, 233. (b) Redlich, H.; Samm, K.; Lenfers, J. B.;
Bruns, W. Carbohydr. Res. 1988, 174, 341.
23. Majewsky, M.; MacKinnon, J. Can. J. Chem. 1994, 72, 1699.
24. Ballester, P.; Garcia-Raso, A.; Mestres, R. Synthesis 1985,
802.