Reaction of the acetals with TESOTf-base combination; speculation of the intermediates and efficient mixed acetal formation

Article abstract of DOI:10.1021/ja060328d

We report here unexpected highly chemoselective deprotection of the acetals from aldehydes. Treatment of acetal compounds from aldehydes with TESOTf-2,6-lutidine or TESOTf-2,4,6-collidine in CH₂-Cl₂ at 0 °C followed by H₂O workup at the same temperature caused the conversion of the acetal functions to aldehyde functions. The reaction had generality and was applied to many acetal compounds. Study using various bases revealed the reaction and reached the best combination of TESOTf-base. It was very mild and highly chemoselective and proceeded under weakly basic conditions. Then, many functional groups such as allyl alcohol, silyl ether, acetate, methyl ether, triphenylmethyl (Tr) ether, 1,3-dithiolane, methyl ester, and tert-butyl ester could survive under these conditions. Furthermore, this methodology could selectively deprotect the acetals in the presence of ketals as the most characteristic feature, although this chemoselectivity is difficult to achieve by other previously reported methods. A detailed study of the reaction including MS and NMR studies revealed the reaction mechanism for determining the structures of the intermediates, pyridinium-type salts. These intermediates had a weak electrophilicity and were successfully applied to the efficient formation of the mixed acetals in high yields.

Full text of DOI:10.1021/ja060328d

Published on Web 04/08/2006
Reaction of the Acetals with TESOTf-Base Combination;
Speculation of the Intermediates and Efficient Mixed Acetal
Formation
Hiromichi Fujioka,* Takashi Okitsu, Yoshinari Sawama, Nobutaka Murata,
Ruichuan Li, and Yasuyuki Kita*
Contribution from the Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6,
Yamada-oka, Suita, Osaka, 565-0871, Japan
Received January 16, 2006; E-mail: fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
Abstract: We report here unexpected highly chemoselective deprotection of the acetals from aldehydes.
Treatment of acetal compounds from aldehydes with TESOTf-2,6-lutidine or TESOTf-2,4,6-collidine in CH2-
Cl2 at 0 °C followed by H2O workup at the same temperature caused the conversion of the acetal functions
to aldehyde functions. The reaction had generality and was applied to many acetal compounds. Study
using various bases revealed the reaction and reached the best combination of TESOTf-base. It was
very mild and highly chemoselective and proceeded under weakly basic conditions. Then, many functional
groups such as allyl alcohol, silyl ether, acetate, methyl ether, triphenylmethyl (Tr) ether, 1,3-dithiolane,
methyl ester, and tert-butyl ester could survive under these conditions. Furthermore, this methodology
could selectively deprotect the acetals in the presence of ketals as the most characteristic feature, although
this chemoselectivity is difficult to achieve by other previously reported methods. A detailed study of the
reaction including MS and NMR studies revealed the reaction mechanism for determining the structures of
the intermediates, pyridinium-type salts. These intermediates had a weak electrophilicity and were
successfully applied to the efficient formation of the mixed acetals in high yields.
Discovery of new chemical species sometimes opens a new
field of chemistry. In this article we report such an example
using the new salts obtained from the unprecedented deprotec-
tion of acetals.
produced after treatment with H2O. After the initial communica-
tion, we investigated the structures of the polar intermediates
and determined them as pyridinium-type salts. We then used
the intermediates for the novel formation of mixed acetals. We
now present the full details of these reactions using new
chemical species, speculation of their intermediates, and the
application for an efficient mixed acetal formation (Scheme 1).
Acetal functions are recognized as good protecting groups
of carbonyl functions and widely used in synthetic organic
chemistry. They are tolerant under neutral and basic conditions.
The acidic conditions are usually used for their deprotection,
and under these conditions, the acetals from ketone functions
(ketals in this text) are usually deprotected more easily than
the acetals from aldehyde functions (acetals in this text) due to
the stability of the cation intermediates.1 Although new methods,
such as the reactions using a catalytic amount of a transition
metal or Lewis acid reagents,2a-c phosphorus2d,e or silicon
reagents,2f,g or DDQ or CAN reagents,2h-j have already been
developed, the development of a mild and chemoselective
deprotection method is strongly desirable. Recently, we found
a novel chemical transformation in which acetals can be
chemoselectively deprotected in the presence of ketals.3 This
was an unprecedented result, because ketals are usually depro-
tected faster than acetals by the reported procedures.1,2,4 In our
reactions, the starting acetals were first changed to very polar
intermediates, and then the corresponding aldehydes were
Deprotection of the Acetals by TESOTf-2,6-Lutidine or
TESOTf-2,4,6-Collidine
Process of the Discovery: For our synthetic study of
scyphostatin,5 we intended the triethylsilylation of the tert-
(2) For selected recent examples on deacetalization, see: (a) Ates, A.; Gautier,
A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C.; Marko´, I. E.
Tetrahedron 2003, 59, 8989-8999. (b) Dalpozzo, R.; De Nino, A.; Maiuolo,
L.; Procopio, A.; Tagarelli, A.; Sindona, G.; Bartoli, G. J. Org. Chem.
2002, 67, 9093-9095. (c) Carrigan, M. D.; Sarapa, D.; Smith, R. C.;
Wieland, L. C.; Mohan, R. S. J. Org. Chem. 2002, 67, 1027-1030. (d)
Eash, K. J.; Pulia, M. S.; Wieland, L. C.; Mohan, R. S. J. Org. Chem.
2000, 65, 8399-8401. (e) Marko´, I. E.; Ates, A.; Gautier, A.; Leroy, B.;
Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed. 1999,
38, 3207-3209. (f) Kaur, G.; Trehan, A.; Trehan, S. J. Org. Chem. 1998,
63, 2365-2366. (g) Marcantoni, E.; Nobili, F. J. Org. Chem. 1997, 62,
4183-4184. (h) Johnstone, C.; Kerr, W. J.; Scott, J. S. Chem. Commun.
1996, 341-342. (i) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. H. J.
Org. Chem. 1986, 51, 404-407. (j) Balme, G.; Gore´, J. J. Org. Chem.
1983, 48, 3336-3338.
(3) Fujioka, H.; Sawama, Y.; Murata, N.; Okitsu, T.; Kubo, O.; Matsuda, S.;
Kita, Y. J. Am. Chem. Soc. 2004, 126, 11800-11801.
(1) (a) Greene, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; pp 297-329.
(b) Hanson, J. R. In Protecting Groups in Organic Synthesis; Blackwell
Science, Inc: Malden, MA, 1999; pp 37-43. (c) Kocienski, P. J. Protecting
Groups; George Thieme Verlag: Stuttgart, 1994; pp 156-170.
(4) (a) Deslongchamps, P.; Dory, Y. L.; Li, S. Tetrahedron 2000, 56, 3533-
3537. (b) Cordes, E. H.; Bull, H. G. Chem. ReV. 1974, 74, 581-603.
(5) Fujioka, H.; Kotoku, N.; Sawama, Y.; Nagatomi, Y.; Kita, Y. Tetrahedron
Lett. 2002, 43, 4825-4828. The manuscript for asymmetric total synthesis
of scyphostatin is in preparation.
9
5930
J. AM. CHEM. SOC. 2006, 128, 5930-5938
10.1021/ja060328d CCC: $33.50 © 2006 American Chemical Society

Acetals with TESOTf−Base Combination
A R T I C L E S
Scheme 1
Scheme 3
Table 2. Examination Using the Compounds with Only Acetal
Functional Group
Scheme 2
Table 1. Examination of the Reaction of 3 with Various Silylating
Reagents
silylating
entry
reagent (equiv)
R
yield (%)
4:5
product
1
2
3
4
5
TESOTf (4.0)
TMSOTf (2.0)
TESCl (4.0)b
TES
98
100
n.r.
90
100:0
100:0
4a
4b
TMS
TMSCl (4.0)b
TBDMSOTf (4.0)
TMS
TBDMS
0:100
0:100
5b
5c
87
enough to complete the reaction. It showed that TMSOTf was
more reactive than TESOTf. However, no reaction occurred by
TESCl, and for the silyl chloride or more bulky tert-butyldim-
ethylsilyl trifluoromethanesulfonate (TBDMSOTf), only the
silylated acetals 5 (R ) TMS or TBDMS) were obtained. With
these silylating reagents no deprotection of the acetal function
afforded 4 (entries 3-5).
The reaction was not promoted by trifluoromethanesulfonic
acid (TfOH), though it was formed by the reaction of the
hydroxyl group and TESOTf or TMSOTf. This was ascertained
by the fact that no reaction occurred by the addition of TfOH
in place of TMSOTf (Scheme 3).
a Equivalent of 2,6-lutidine is 1.5 times to silylating reagent. b Reaction
was carried out at room temperature for 24 h.
alcohol of cyclohexene alcohol 1 with an acetal from an
aldehyde. When the reaction was carried out using triethylsilyl
trifluoromethanesulfonate (TESOTf) (4.0 equiv) and 2,6-lutidine
(6.0 equiv), the silylated aldehyde 2 was obtained in good yield
under mild conditions (0 °C) (Scheme 2). This was an
unexpected result, because the deprotection of acetals from
aldehydes usually needs rather drastic acidic conditions. This
fact suggested that the reaction proceeds through an unusual
process. We then studied the reaction in detail.
Reactions of Various Acetals: Hydroxyl dimethyl acetal 3
was used as the substrate for this detailed study. Table 1 shows
the combinations of the various silylating reagents and 2,6-
lutidine.6 The combination of TESOTf and 2,6-lutidine also
produced the triethylsilylated aldehyde 4a (R ) TES) at 0 °C
for 0.5 h. This fact showed that the reaction condition had the
generality for the deprotection of acetals from aldehydes (entry
1). The use of trimethylsilyl trifluoromethanesulfonate (TM-
SOTf) also caused the hydrolysis of the acetal and produced
trimethylsilylated aldehyde 4b (R ) TMS) (entry 2).7 In this
case, 2.0 equiv of TMSOTf and 3.0 equiv of 2,6-lutidine were
Two silylating reagents, TESOTf and TMSOTf, which were
effective for the deprotection of the dimethyl acetal from an
aldehyde having a hydroxyl group, were next examined using
compounds with only the acetal functional group (Table 2).
Although two reagents were similarly effective with the dimethyl
acetals 6a and the dioxolane 6b to give the aldehyde 7 (entries
1-4), a difference was observed in the reactions of the dioxane
6c. Thus, TMSOTf gave the deprotected aldehyde 7, though it
required a longer reaction time (entry 6), whereas TESOTf gave
the enol silyl ether 8 in good yield (entry 5). The remarkable
feature and the most interesting difference between the two
reagents were exemplified in the reactions of the ketal 9.
Although TMSOTf produced the deprotected ketone 10 in 1 h
via enol ether intermediate (TLC) (entry 8), TESOTf did not
work well and the formation of only a trace amount of 10 was
observed even after 6 h and starting material 9 was recovered
(entry 7). These results, especially those of entries 3 and 7,
suggested that the combination of TESOTf-2,6-lutidine could
realize the unprecedented chemoselective deprotection of acetals
in the presence of ketals (vide infra).
(6) For a review of TMSOTf, see: Emde, H.; Domsch, D.; Feger, H.; Frick,
U.; Go¨ts, A.; Hergott, H. H.; Hofmann, K.; Kober, W.; Kra¨geloh, K.;
Oesterle. T.; Steppan, W.; West, W.; Simchen, G. Synthesis 1982, 1-26.
For TESOTf, see: (a) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli,
R.; Badertscger, U. J. Org. Chem. 1985, 50, 2095-2105. (b) Hart, T. W.;
Metcalfe, D. A.; Scheinmann, F. J. Chem. Soc., Chem. Commun. 1979,
156-157.
(7) We regret our oversight in not locating and for not citing in our
communication the reports that the combination of TMSOTf-2,6-lutidine
caused the transformation of an acetal into an aldehyde in a natural product
synthesis; Meert, C.; Wang, J.; De Clercq, P. J. Tetrahedron Lett. 1997,
38, 2179-2182. Wang, J.; De Clercq, P. J. Angew. Chem., Int. Ed. Engl.
1995, 34, 1749-1752.
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A R T I C L E S
Fujioka et al.
Table 3. Study of Various Bases for Deprotection of Acetal 6a
Scheme 4
To clarify the effect of base, various types of aromatic bases
were next examined using the acetal 6a, which has only the
acetal function (Table 3). The reactions were carried out under
the combination of TESOTf (2.0 equiv)-base (3.0 equiv). The
nonbase condition proved that the base is necessary (entry 1).
An interesting tendency was observed that depended on the type
of base. Pyridine and 2-picoline formed very stable polar
compounds, which were not transformed into 7 even by a long
H2O workup (24 h) (entries 2, 3). On the other hand, 2,6-lutidine,
which has one more methyl group at the C6 position of
2-picoline, gave the deprotected aldehyde 7 in good yield for
short H2O treatment (0.1 h) (entry 4). These facts showed that
the bulkiness of the base was very important for promoting this
transformation. In fact, 2,4-lutidine, which is a regioisomer of
2,6-lutidine, with the bulkiness of its C2- and C6-positions being
smaller than that of 2,6-lutidine, afforded a very stable polar
compound, which was not transformed into 7 even by a long
H2O workup (24 h) (entry 5). This shows that the success of
the reaction needs the appropriate bulkiness of the bases. Two
bases were next examined. As expected, 2,4,6-collidine, which
has one more C4-methyl group than 2,6-lutidine, afforded the
deprotected aldehyde 7 in excellent yield, though the polar
compound is more stable than that from 2,6-lutidine and a
slightly longer H2O workup (0.5 h) was necessary (entry 6).
On the contrary, 4-(dimethylamino)pyridine (4-DMAP) did not
work at all, and no reaction occurred (entry 7). The reason for
this result is still unclear.
The reactivity of the combination of TESOTf-2,6-lutidine
was next examined in various acetals. Table 4 shows the results
of the various acetals. The aromatic acetal 11, R,â-unsaturated
acetal 13, and acetal 15 next to the secondary carbon center
also could be deprotected in good yields (entries 1-3). This
reaction is very mild, and many functional groups such as acetate
17a, methyl ether 17b, triphenylmethyl (Tr) ether 17c, 1,3-
dithiolane 19, methyl ester 21a, and tert-butyl ester 21b could
survive under these conditions (entries 4-9). The compounds
23 and 25 having a hydroxyl function needed more reagents
(entries 10 and 11). Among the acetals in Table 4, the
compounds which gave rather low yields of products were
treated with TESOTf-2,4,6-collidine, and better yields were
obtained (entries 2, 3, 7, 11, and 12).
producing more stable oxonium ions (ketals) are more easily
deprotected than those producing the less stable oxonium ions
(acetals).4 In fact, for example, Kreevoy et al. reported that the
relative rate of hydrolysis of the ketal, (CH3)2C(OEt)2, is 1.83
× 107 times that of the acetal, CH2(OEt)2.8 As mentioned above,
it is widely recognized that ketals are deprotected much faster
than acetals. On the other hand, our method, which deprotects
acetals faster than the ketals, was unprecedented. Therefore, the
results in Table 2, especially when the acetal in entry 3 is
deprotected faster than ketal in entry 7 by TESOTf-2,6-lutidine,
were in contrast to those found by the reported methods.
The high chemoselectivity of the TESOTf-2,6-lutidine
combination was apparent from the following experiments.
Among the three acyclic acetals 6d-f examined, only the diethyl
acetal 6d was deprotected to give the aldehyde 7, whereas other
acetals, i.e., diisopropyl acetal 6e and dibenzyl acetal 6f, were
not affected at all under the stated condition (Scheme 4). The
same tendency was observed using 2,4,6-collidine. This fact
and the results in Table 2 (entries 3 and 7) showed that a steric
factor was very important in these reactions. This was also
featured by the treatment of a 1:1 mixture of the acetal 27 and
ketal 9. Thus, the mixture afforded 82% of the aldehyde 28
from the acetal 27 with the recovered ketal 9 using 2,6-ludidine.
The use of 2,4,6-collidine also afforded the quantitative yield
of 28 and recovered 9.
Furthermore, compound 29 having acetal and ketal units in
the molecule was examined (Table 5). Our method selectively
gave the ketal aldehyde 30 in good yield (entries 1, 2), whereas
other representative methods such as the aq. p-TsOH or TMSI
treatment did not produce any deacetalized product 30 (entries
3 and 4).9,10
Table 6 shows the results from the acetals having an acetal
and a ketal unit together. In every entry, the major product was
the one obtained by the selective acetal deprotection. In the cases
of entries 4 and 5, the substrates had an additional hydroxyl
function, and the TES-ether aldehyde ketals were obtained as
major products. For the rather low yields of products (entries 2
(8) Kreevoy, M. M.; Taft, R. W., Jr. J. Am. Chem. Soc. 1955, 77, 5590-5595.
See also: Bunton, C. A.; De Wolfe, R. H. J. Org. Chem. 1965, 30, 1371-
1375.
High Chemoselectivity: The rate-determining step of the
transformation of acetals to carbonyl compounds is the cleavage
step of the C-O bond of the acetals. The stabilities of the
oxonium ions formed by the cleavage of the C-O bond of the
acetals would then affect the reaction rate. Namely, acetals
(9) Jung, M. E.; Andrus, W. A.; Ornstein, P. L. Tetrahedron Lett. 1977, 4175-
4178.
(10) For examples in which aliphatic ketals are selectively deprotected in the
presence of aliphatic acetals, see: (a) entry 8 of Table 1 in ref 2g. (b)
Ukaji, Y.; Koumoto, N.; Fujisawa, T. Chem. Lett. 1989, 1623-1626.
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5932 J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006

Acetals with TESOTf−Base Combination
A R T I C L E S
Table 4. Mild Deprotection of Various Acetals
a TESOTf (3.0 equiv) and base (4.0 equiv) were used. b TESOTf (4.0 equiv) and base (6.0 equiv) were used.
Table 5. Comparison of Our Method with Other Methods
as a Lewis acid and can easily transform them into oxonium
ions, which are strong electrophiles. It then works as an efficient
catalyst for nucleophilic addition toward the acetal (Scheme 5,
route a).6 On the other hand, the attack of water on the oxonium
ions can produce a carbonyl compound (route b). However
TfOH is simultaneously produced in route b, and the reaction
mixture becomes strongly acidic which results in moderate
yields of the products (for example, see Scheme 6).
In fact, Trehan et al. reported that the deprotection of the
acetal by TMSOTf gave the product in moderate yields.11 Our
result, entry 1 of Table 3, also showed that the use of TESOTf
only produced poor results. On the other hand, as mentioned
above, the combination of TESOTf-2,6-lutidine could deprotect
acetals from aldehydes in good yields (for the benzaldehyde
dimethyl acetal result, see Table 4, entry 1) (Scheme 6). Since
the reaction proceeds under weakly basic conditions, many acid-
labile functional groups could tolerate the reaction. Furthermore,
highly polar compounds were first formed, and an H2O workup
entry
method (equiv)
condition
yield (%)
30:31:32
1
TESOTf (2.0)
2,6-lutidine (3.0)
TESOTf (2.0)
2,4,6-collidine (3.0) then H2O
p-TsOH (1.0)
CH2Cl2, 0 °C 1 h,
then H2O
CH2Cl2, 0 °C 1 h,
79
100:0:0
2
3
4
83a
80
100:0:0
0:90:10
0:77:23
acetone/H2O ) 1:1,
rt, 3.5 h
CH2Cl2, 0 °C 1 h
TMSI (1.0)
94
a Based on recovered starting material.
and 3), the use of 2,4,6-collidine tended to give the desired
products in higher yields.
Reaction and Speculation of the Intermediate
Discussion about the Reaction Mechanism and Chemose-
lectivity: Generally, trialkylsilyltriflate works on acetals such
(11) See: Kaur, G.; Trehan, A.; Trehan, S. J. Org. Chem. 1998, 63, 3, 2365-
2366, ref 9.
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A R T I C L E S
Fujioka et al.
Table 6. Chemoselective Deprotection of Substrates Having Acetal and Ketal Units
a TESOTf (2.0 equiv) and base (3.0 equiv) were used.
Scheme 5
Scheme 6
Scheme 7
was necessary to produce the deprotected carbonyl compounds.
These facts showed the unusual reaction path and new reaction
intermediate.
yield. Therefore, we determined that the polar compound 39
was a pyridinium salt.
The Reaction Mechanism and the Structure of the Polar
Compounds (NMR and MS Studies). The polar compound
from the reaction of the acetal 6a and pyridine (Table 3, entry
2) was first isolated. Thus, azeotropic distillation of the reaction
mixture with benzene in vacuo removed CH2Cl2, H2O, and
pyridine to give the residue, which was dissolved in hexane/
MeOH (1:9). The hexane layer containing the less polar
component was removed, and evaporation of the MeOH layer
afforded the polar compound 39 (Scheme 7). Its 1H NMR
spectrum showed the presence of three aromatic protons (δ:
9.10, 8.61, 8.18), an acetal proton (δ: 6.03), and one methoxy
proton (δ: 3.50). Its 19F NMR showed the presence of a fluorine
atom (δ: -79.59). The high-resolution FABMS of 39 showed
that its composition formula was C16H28NO. Aqueous acidic
treatment of 39 gave the deprotected aldehyde 7 in quantitative
Based on the consideration of the result using pyridine, we
postulated that the polar compound in the 2,6-lutidine reaction
was similar to the lutidinium salt. As expected, the FABMS of
the reaction mixture showed the M+ peak of the 2,6-lutidinium
1
salt 40 at 278 m/z (Scheme 8). An H NMR spectrum of the
reaction is shown in Figure 1. Chart A is the 1H NMR chart of
2,6-lutidine. Chart B is the 1H NMR chart of the acetal 6a. Chart
C is the 1H NMR chart of the reaction mixture obtained by the
treatment of 6a with TESOTf (2.0 equiv) and 2,6-lutidine (3.0
equiv). The characteristic acetal proton around δ 6.0 ppm
suggested the N,O-acetal structure and no proton from an
aldehyde were observed in Chart C. However, the H2O workup
of the mixture resulted in the disappearance of the proton around
δ 6.0 ppm and the formation of the new proton of an aldehyde
around δ 9.75 ppm (Chart D). Additionally, similar reaction
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Acetals with TESOTf−Base Combination
A R T I C L E S
Scheme 8. Study on the Reaction Intermediate 40 by FAB(+)MS
1
Figure 1. Study on the reaction mechanism by H NMR.
intermediates were also observed for the reaction under TESOTf-
2,4,6-collidine conditions. Chart E is the 1H NMR chart of the
reaction mixture obtained by the treatment of 6a with TESOTf
(2.0 equiv) and 2,4,6-collidine (3.0 equiv), and not 2,6-lutidine.
In this case, the peak due to the N,O-acetal also newly appeared
around 6.0 ppm, and Chart E is very similar to Chart C.
Although Roush et al. succeeded in the intramolecular trans-
acetalization of MOM ether under identical conditions and
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J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5935

A R T I C L E S
Scheme 9
Fujioka et al.
Scheme 10
they reported that their transacetalization was activated by
TfOH,12 in our case, TfOH is not effective (see Scheme 3).
Therefore, we consider that our genuine species are different
from theirs.13 This conclusion also proved to be possible from
the observation that the intermediates worked as good pre-
cursors for the efficient mixed acetal formation (see next
chapter).
the allyltrimethylsilane, gave the mixed acetals 42 and 43 in
high yields (Scheme 10). These results meant that the colli-
dinium salts have a very weak electrophilicity and only strong
nucleophiles, such as water and alcohols, can react with the
salts.
Although several studies are reported for the preparation of
mixed acetals, most of them use an acid catalyst. Therefore,
the yields of the desired mixed acetals are moderate due to the
over-reaction. On the other hand, our method proceeds under
weakly basic conditions and is quite good for making mixed
acetals such as 42 and 43. We then applied the method to the
other mixed acetals, which were obtained in moderate yields
in the previous studies (Scheme 11). Thus, the treatment of
dimethyl acetal 44 with TESOTf and 2,4,6-collidine followed
by the addition of geraniol gave the mixed acetal 45 in 87%
yield, whereas the yield of the previous report was 57%.15 For
the same procedure, the mixed acetal 47 was obtained from 46
in 91% yield (the reported yield was 81%).16 Although the
dimethyl acetal 48 has acid-sensitive functional groups, the
better yield of 79% than the reported yield of 67%17 was
obtained to give the mixed acetal 49.
Based on this study, a plausible reaction mechanism is shown
in Scheme 9. Thus the attack of 2,6-lutidine or 2,4,6-collidine
on the acetal function activated by a Lewis acid resulted in the
formation of the pyridinium-type salt 40 close to the pyridinium
salt 39. However, the stability of 40 was completely different
from 39. 40 was a very unstable compound because of the steric
hindrance of the 2,6-dimethyl groups of 2,6-lutidine or 2,4,6-
collidine and very reactive with water. Easy cleavage of the
C-N bond followed by attack of H2O then afforded the
deprotected aldehyde 7. At the same time, excess 2,6-lutidine
or 2,4,6-collidine could capture the simultaneously formed
trifluoromethanesulfonic acid. The reactions then proceeded
under weakly basic conditions.
Efficient Mixed Acetal Formation: The properties of the
collidinium salt converted to nucleophiles were examined. The
reaction process was as follows. After the disappearance of 6a
on TLC by treatment with TESOTf (2.0 equiv)-2,4,6-collidine
(3.0 equiv), 3.0 equiv of the nucleophile were added to the
mixture. The use of allyltrimethylsilane,14 a very popular
nucleophile for oxonium ions, did not give the allylated product
41, and an aldehyde 7 was obtained after H2O workup, whereas
the use of EtOH and allyl alcohol, stronger nucleophiles than
These results show that our method for the mixed acetal
synthesis is very mild and superior to the previous methods.
Conclusion
We have developed a new deprotection method of acetals
from aldehydes via pyridinium-type intermediates. The method
is very sensitive to the steric morphology of the acetals and
can produce the unprecedented, unexpected, and remarkably
high chemoselective deprotection method. This methodology
can selectively deprotect the acetals in the presence of ketals,
although this chemoselectivity is difficult to achieve by other
previously reported methods. A detailed study of the method
using various bases and spectroscopic examination of the
(12) For the intramolecular transacetalization of MOM ether under identical
conditions, see: (a) Durharm, T. B.; Blanchard, N.; Savall, B. M.; Powell,
N. A.; Roush, W. R. J. Am. Chem. Soc. 2004, 126, 9307-9317. (b) Powell,
N. A.; Roush, W. R. Org. Lett. 2001, 3, 453-456.
(13) TESOTf from ACROS ORGANICS was used in our experiments. When
the reaction of 6a was conducted by the all-distilled reagents (TESOTf,
2,4,6-collidine, and CH2Cl2), the same result was obtained. This fact shows
that the reaction is not catalyzed by trace amounts of TfOH.
(14) For the reaction of allyltrimethylsilane and acetals mediated by TMSOTf,
see: Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 71-
74.
(15) Baeckstrom, P.; Li, L. Tetrahedron 1991, 47, 6521-6532.
(16) Isidor, J. L.; Carlson, R. M. J. Org. Chem. 1973, 38, 554-556.
(17) Bi, L.; Zhao, M.; Wang, C.; Peng, S. Eur. J. Org. Chem. 2000, 2669-
2676.
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5936 J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006

Acetals with TESOTf−Base Combination
A R T I C L E S
Scheme 11
the disappearance of 29 on TLC, sat. NaHCO3 aq. and sat. Na2S2O3
aq. were successively added to the mixture at 0 °C. The mixture was
extracted with CH2Cl2. The organic layer was dried over Na2SO4,
filtered, and evaporated in vacuo. The residue was purified by flash
SiO2 column chromatography using hexanes-Et2O (2:1) to give a
mixture of 31 and 32 (46.9 mg, 94%, the ratio of 31 and 32 was
reaction revealed the reaction mechanism for determining the
structures of the intermediates. These intermediates had a weak
electrophilicity and were successfully applied to the efficient
formation of the mixed acetals in high yields. The reaction is a
new one via new intermediates, and its further application in
synthetic organic chemistry is under investigation.
1
determined by H NMR).
Experimental Section
Pyridinium Salt 39 and Its Hydrolysis in Scheme 7: Pyridine (60
µL, 0.74 mmol) was added to a solution of 6a (50.2 mg, 0.25 mmol)
in CH2Cl2 (2.4 mL) at 0 °C under N2. After the solution was stirred
for 5 min, TESOTf (112 µL, 0.50 mmol) was dropwise added. The
mixture was stirred at 0 °C. After the disappearance of 6a (TLC check),
the reaction was quenched by the addition of H2O. The mixture was
then evaporated in vacuo. The residue was further coevaporated with
benzene. The residue was diluted with hexane-MeOH (1:9). The
MeOH layer was dried over Na2SO4 and evaporated in vacuo to give
39 (89.4 mg, 92%). PPTS (2.5 mg, 0.01 mmol) was added to a solution
of 39 (56.6 mg, 0.14 mmol) in acetone-H2O (v/v ) 1/1, 2.0 mL). The
mixture was stirred for 2 h. The solution was poured into sat. aq.
NaHCO3 and extracted with Et2O. The organic layer was dried over
Na2SO4 and evaporated in vacuo. The residue was purified by SiO2
column chromatography using hexane-CH2Cl2 (3:2) as the eluent to
give 7 (21.8 mg, quant). 1-(1-Methoxydecyl)pyridinium Trifluo-
romethanesulfonate (39): Colorless oil; 1H NMR (CDCl3) δ 9.10
(d, J ) 5.4 Hz, 2H), 8.61 (t, J ) 7.8 Hz, 1H), 8.18 (dd, J ) 7.8,
5.4 Hz, 2H), 6.03 (t, J ) 5.1 Hz, 1H), 3.50 (s, 3H) 1.94 (m, 2H),
1.23 (m, 14H), 0.87 (t, J ) 6.6 Hz, 3H); 13C NMR (CDCl3) δ 147.0
(2C), 141.0, 128.7(2C), 102.0, 58.5, 38.0, 31.7, 29.3, 29.2, 29.1, 28.8,
24.1, 22.6, 14.0; 19F NMR (CDCl3) δ -79.59 (C6F6 as internal
standard). HRFABMS: calcd for C16H28NO (M+), 250.2171; found,
250.2174.
General Reaction Procedure Using TESOTf-2,6-Lutidine (or
2,4,6-Collidine): First, 2,6-lutidine (or 2,4,6-collidine) (3.0 equiv for
the compounds having only acetal function and 4.0 equiv for the
compounds having hydroxyl and acetal functions) and, second, TESOTf
(2.0 equiv for the compounds having only acetal function and 3.0 equiv
for the compounds having hydroxyl and acetal functions) were added
to a solution of an acetal in CH2Cl2 (0.1 M solution) at 0 °C under N2
gas. The mixture was stirred at the same temperature. After checking
for the disappearance of an acetal on TLC, H2O was added to the
resulting mixture and stirred. Disappearance of the polar component
was ascertained by TLC. The mixture was extracted with CH2Cl2. The
organic layer was dried over Na2SO4, filtered, and evaporated in vacuo.
The residue was purified by flash SiO2 column chromatography to
produce the aldehyde.
Deprotection Reaction of 29 with TESOTf-2,6-lutidine, p-TsOH,
and TMSI (Table 5). A. TESOTf-2,6-Lutidine: 2,6-Lutidine (55
µL, 0.48 mmol) and TESOTf (72 µL, 0.32 mmol) were added to a
solution of 29 (48.0 mg, 0.16 mmol) in CH2Cl2 (1.6 mL) at 0 °C under
N2 gas. The mixture was stirred for 1 h at the same temperature. After
the disappearance of 29 was checked on TLC, H2O was added to the
resulting mixture and stirred. The disappearance of the polar component
was ascertained by TLC. All procedures were done at 0 °C. The mixture
was extracted with CH2Cl2. The organic layer was dried over Na2SO4,
filtered, and evaporated in vacuo. The residue was purified by flash
SiO2 column chromatography using hexanes-Et2O (7:1) to give 30
(32.5 mg, 79%).
Experiment in Scheme 8: 2,6-Lutidine (40 µL, 0.34 mmol) was
added to a solution of 4a (25.0 mg, 0.11 mmol) in CH2Cl2 (0.1 mL) at
0 °C under N2. After the solution was stirred for 5 min, TESOTf (52
µL, 0.23 mmol) was dropwise added. The mixture was stirred for 30
min. The solution was directly measured by FAB(+)MS.
General Procedure for the Synthesis of Mixed Acetals. 2,4,6-
Colldine (3.0 equiv) and TESOTf (2.0 equiv) were added to a solution
of an acetal in CH2Cl2 (0.1 M solution) at 0 °C under N2. The mixture
was stirred at the same temperature. After checking for the disap-
pearance of the acetal by TLC, an alcohol (1.5 equiv) was added
to the resulting mixture and stirred at rt. Disappearance of the
polar component was ascertained by TLC. The mixture was quenched
with water and extracted with CH2Cl2. The organic layer was
dried over Na2SO4, filtered, and evaporated in vacuo. The residue was
purified by flash SiO2 column chromatography to give the mixed
acetal.
B. p-TsOH: p-TsOH (5.8 mg, 0.03 mmol) was added to a solution
of 29 (19.3 mg, 0.03 mmol) in acetone-H2O (1:1)(0.6 mL), and the
resulting mixture was stirred at rt for 3.5 h. After checking for the
disappearance of 29 on TLC, sat. NaHCO3 aq. was added to the mixture
at 0 °C. The resulting solution was evaporated to remove the acetone
in vacuo. The mixture was extracted with Et2O. The organic layer was
dried over Na2SO4, filtered, and evaporated in vacuo. The residue was
purified by flash SiO2 column chromatography using hexanes-Et2O
(2:1) to give a mixture of 31 and 32 (13.2 mg, 80%, the ratio of 31
1
and 32 was determined by H NMR).
C. TMSI: TMSI (29 µL, 0.20 mmol) was added to a solution of
29 (60.6 mg, 0.20 mmol) in CH2Cl2 (2.0 mL) at 0 °C under N2 gas.
The resulting mixture was stirred at 0 °C for 1 h. After checking for
9
J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5937

A R T I C L E S
Fujioka et al.
Acknowledgment. This work was supported by Grant-in-
Aid for Scientific Research (S) and Grant-in-Aid for Scientific
Research for Exploratory Research from Japan Society for the
Promotion of Science and by Grant-in-Aid for Scientific
Research on Priority Areas (17035047) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: Full experimental details
including the physical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA060328D
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5938 J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006