Organic chemistry using weakly electrophilic salts: Efficient formation of O,O-mixed, O,S- and N,O-acetals

Article abstract of DOI:10.1021/jo071187g

(Chemical Equation Presented) A mild and efficient method for the preparation of O,O-mixed, O,S- and N,O-acetals from symmetrical O,O-acetals has been developed. Thus, the treatment of symmetrical O,O-acetals with TESOTf and 2,4,6-collidine formed weakly

Full text of DOI:10.1021/jo071187g

Organic Chemistry Using Weakly Electrophilic Salts: Efficient
Formation of O,O-Mixed, O,S- and N,O-Acetals
Hiromichi Fujioka,* Takashi Okitsu, Takuya Ohnaka, Ruichuan Li, Ozora Kubo,
Kazuhisa Okamoto, Yoshinari Sawama, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6, Yamada-oka, Suita,
Osaka 565-0871, Japan
fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
ReceiVed June 5, 2007
A mild and efficient method for the preparation of O,O-mixed, O,S- and N,O-acetals from symmetrical
O,O-acetals has been developed. Thus, the treatment of symmetrical O,O-acetals with TESOTf and 2,4,6-
collidine formed weakly electrophilic collidinium salts. The addition of nucleophiles, such as an alcohol,
lithium thioxide, and sodium azide, to the salts afforded the corresponding O,O-mixed, O,S- and N,O-
acetals in good yields. The reaction proceeded under weakly basic conditions. No overreaction then
occurred and many acid-labile functional groups could remain intact.
SCHEME 1
Introduction
Recently, we developed a novel chemical transformation in
which acetals can be chemoselectively deprotected in the
presence of ketals,1 whereas the reported procedures2 usually
deprotect ketals faster than acetals. We also found that the
reaction proceeded via polar intermediates and determined them
to be pyridinium-type salts1b,c (Scheme 1).
The properties of the collidinium salt (R′ ) Me, Scheme 1)
are as follows: The salt does not react with the allyltrimeth-
ylsilane, a very popular nucleophile for oxonium ions, whereas
it reacts with EtOH and allyl alcohol in high yields (Scheme
2). These results suggest that the collidinium salts have a weak
electrophilicity, and strong nucleophiles, such as water, alcohols,
and Gilman reagents,3 can react with these salts. Another
SCHEME 2
(1) (a) Fujioka, H.; Sawama, Y.; Murata, N.; Okitsu, T.; Kubo, O.;
Matsuda, S.; Kita, Y. J. Am. Chem. Soc. 2004, 126, 11800-11801. (b)
Fujioka, H.; Okitsu, T.; Sawama, Y.; Murata, N.; Li, R.; Kita, Y. J. Am.
Chem. Soc. 2006, 128, 5930-5938. (c) Fujioka, H.; Okitsu, T.; Ohnaka,
T.; Sawama, Y.; Kubo, O.; Okamoto, K.; Kita, Y. AdV. Synth. Catal. 2007,
349, 636-646.
(2) (a) Greene, T. W.; Wuts, P. G. Protecting Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999. (b) Hanson, J.
R. Protecting Groups in Organic Synthesis, 1st ed.; Blackwell Science,
Inc: Malden, MA, 1999. (c) Kocienski, P. J. Protecting Groups, 1st ed.;
George Thieme Verlag: Stuttgart, 1994.
characteristic feature is that the reaction proceeds under weakly
basic conditions. On the basis of these advantages, we reported
the O,O-mixed acetal formations using this method.1b
This unique, attractive, and interesting reaction allowed us
to develop further application, in particular, the reactions of the
2,4,6-collidinium salt with various heteronucleophiles. Herein,
(3) Fujioka, H.; Okitsu, T.; Sawama, Y.; Ohnaka, T.; Kita, Y. Synlett
2006, 18, 3077-3080.
10.1021/jo071187g CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/21/2007
7898
J. Org. Chem. 2007, 72, 7898-7902

Organic Chemistry Using Weakly Electrophilic Salts
TABLE 1. Reaction of Acetal 1a with Various Alcohols
TABLE 2. Reaction of Acetals 1b-h with Allyl Alcohol
a TESOTf (3.0 equiv), 2,4,6-collidine (4.0 equiv), and allyl alcohol (2.5
equiv) were used.
a A 5:4 diastereomeric mixture.
as allyl alcohol, propargyl alcohol, and benzyl alcohol, which
easily form cation species by the SN1-type elimination of the
hydroxyl group under acidic conditions, did not cause any
problem and afforded the corresponding O,O-mixed acetals in
high yields (entries 2-4). Secondary and tertiary alcohols also
gave the mixed acetals in high yields (entries 5-7), although
sterically hindered alcohols usually cannot react with acetals.6i
Furthermore, the alcohols with acid-labile functional groups,
such as an epoxide (entry 8), dimethyl acetal (entry 9), and a
sugar unit (entry 10), gave the corresponding mixed acetals in
sufficient yields. The results in Table 1 suggested that the use
of sterically hindered ones (entries 7 and 10) needed a longer
reaction time to consume the collidinium salt. Even acetic acid
and phenol worked as nucleophiles and gave the corresponding
mixed acetal-type products (71% in the case of acetic acid, 64%
in the case of phenol), although they also needed longer reaction
times (60 min for each reaction) to consume the collidinium
salt.
We next examined the reaction with various starting acetals
and the allyl alcohol as a nucleophile. The results are shown in
Table 2. Diethyl acetal (entry 1), dioxolane (entry 2), and the
dimethyl acetal having a secondary carbon (entry 3) afforded
the desired mixed acetals. Dimethyl acetals having various
functional groups were also available for this reaction (entries
4-7). It is noteworthy that acid-labile protective groups, such
as TBS (tert-butyldimethylsilyl) ether and trityl (triphenylm-
ethyl) ether, are not affected under the stated conditions (entries
6 and 7). Since the previously reported methods for mixed acetal
formations under acidic conditions were difficult to produce the
mixed acetals with acid-labile functional groups, these results
show the advantage of our method, which proceeds under
weakly basic conditions.
we present the novel formation of O,O-mixed acetals, O,S-
acetals, and N,O-acetals, which occurs under basic conditions
and in a highly chemoselective manner.
Results and Discussion
Efficient Formation of O,O-Mixed Acetals: O,O-Mixed
acetals are recognized as the synthetic equivalents of esters and
are widely used in many reactions, such as the Diels-Alder
reaction4 and radical cyclization5 for avoiding dipole repulsion.
Although several studies reported the preparation of mixed
acetals, most of them are limited to the methods for the
transacetalization of symmetrical acetals with an alcohol in the
presence of a Lewis acid catalyst.6 Therefore, the yields of the
desired mixed acetals are moderate due to the overreaction.
Furthermore, previously reported acidic methods are not ap-
plicable to compounds having acid-labile functional groups.
On the other hand, our method proceeded under weakly basic
conditions and is quite good for the preparation of O,O-mixed
acetals, as shown in Scheme 2. We then examined the generality
of the method using various alcohols (Table 1). The reaction
process is as follows. After the acetal 1a disappeared by
treatment with TESOTf (2.0 equiv)/2,4,6-collidine (3.0 equiv),
the alcohol (1.5 equiv) was added to the mixture. Alcohols, such
(4) Boeckman, R. K., Jr.; Flann, C. J. Tetrahedron Lett. 1983, 24, 5035-
5038.
(5) For recent examples, see: (a) Affo, W.; Ohmiya, H.; Fujioka, T.;
Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K.; Imamura, Y.; Mizuta,
T.; Miyoshi, K. J. Am. Chem. Soc. 2006, 128, 8068-8077. (b) Miura, K.;
Ootsuka, K.; Hosomi, A. Synlett 2005, 3151-3153. (c) Yamada, R.; Obika,
S.; Nishimori, N.; Yamaguchi, M.; Takemoto, Y. Tetrahedron Lett. 2004,
45, 2331-2334.
(6) For selected examples on mixed acetal formation, see: (a) Isidor, J.
L.; Carlson, R. M. J. Org. Chem. 1973, 38, 554-556. (b) Boeckman, R.
K., Jr.; Flann, C. J. Tetrahedron Lett. 1983, 24, 4923-4926. (c) Overman,
L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110, 2248-2259. (d)
Baeckstro¨m, P.; Li, L. Tetrahedron 1991, 47, 6521-6532. (e) Kitahara,
T.; Warita, T.; Abe, M.; Seya, M.; Takagi, Y.; Mori, K. Agric. Biol. Chem.
1991, 55, 1013-1017. (f) Panda, J.; Ghosh, S. Tetrahedron Lett. 1999, 40,
6693-6694. (g) Bi, L.; Zhao, M.; Wang, C.; Peng, S. Eur. J. Org. Chem.
2000, 2669-2676. (h) Nomura, M.; Shuto, S.; Matsuda, A. Bioorg. Med.
Chem. 2003, 11, 2453-2461. (i) Ledneczki, I.; Molna´r, A. Synth. Commun.
2004, 34, 3683-3690.
A comparison of our method with the previously reported
ones has already been reported.1b Summary of the results, the
yields of the prepared mixed acetals 4-6, is shown in Figure
1. Values of the top are the yields by our method. Those of the
bottom are the yields by other methods: the mixed acetal 4
was obtained from dimethyl acetal and geraniol (H3PO4,
HCO2H, xylene, 140 °C);6d the mixed acetal 5 was obtained
from diethyl acetal and 2,2,2-trichloroethanol (p-TsOH‚H2O,
J. Org. Chem, Vol. 72, No. 21, 2007 7899

Fujioka et al.
TABLE 3. Reaction of Acetal 1a with Various Thiols
time
(min)
yield
(%)
FIGURE 1. Comparison of the yields of the mixed acetals by our
entry
RSX
product
method and the reported ones.
1
EtSH
40
105
60
75
120
5
7aA
7aB
7aC
7aD
7aE
7aE
89
66
54
61
69
quant
2
iPrSH
tBuSH
BnSH
PhSH
PhSLic
SCHEME 3
3a
4
5
6b
a 2.5 equiv of tBuSH was added. b 3.0 equiv of PhSLi was added. c 1.0
M in THF solution was used.
SCHEME 4
chemistry.7 They are usually prepared by transacetalization in
the presence of a Lewis acid.8,9 Their preparation methods were
limited to acidic conditions, so we applied our method to the
formation of the O,S- and N,O-acetals.
In the beginning, the formation of O,S-acetals 7aA-aE was
examined by the addition of various thiols to the collidinium
salt intermediate (Table 3). The primary thiol gave the desired
product in good yield (entry 1), whereas the secondary, tertiary,
and benzyl thiols afforded the O,S-acetals in moderate yields
(entries 2-4). Although the use of thiophenol also resulted in
a moderate yield (entry 5), the use of its lithium salt (PhSLi)
improved the yield and the reaction time (entry 6).
benzene, 81 °C);6a the mixed acetal 6 was obtained from
dimethyl acetal and ethanol (concd HCl aq, CHCl3, rt).6g In
every case, our result is superior to the reported one. These facts
show that our method for the mixed acetal synthesis is very
mild and superior to the previous methods.
As a nitrogen nucleophile, we chose azidation reagents, such
as NaN3 and trimethylsilyl azide (TMSN3).10 As mentioned
above about the procedure, after the disappearance of the starting
1a, the azidation reagent was added (Table 4). However, almost
no reaction occurred for both reagents (entries 1 and 3). We
then examined the optimized conditions to obtain the N,O-acetal
8aA. In the case of using sodium azide, the use of a crown
ether as an additive produced the N,O-acetal in excellent yield
(entry 2). On the other hand, in the case of TMSN3, tetrabuty-
lammonium difluorotriphenylsilicate (TBAT) was the best
additive (entry 5). However, the yield was less than that of NaN3.
Finally, we determined that the combination of NaN3 and 18-
crown-6 was the most efficient method for the formation of the
N,O-acetals (entry 2).
We would like to now discuss the mixed acetal formation
from a mechanistic point of view.
For the mixed acetal formation, the protocol is as follows.
Acetal A was treated with TESOTf (2.0 equiv) and 2,4,6-
collidine (3.0 equiv) first. After disappearance of A (checked
by TLC), the alcohol (R2OH, 1.5 equiv) was added to the
mixture to give the mixed acetal B in high yield (Scheme 3).
Our previous study shows the formation of the 2,4,6-
collidinium salt intermediate C by the reaction of A with
TESOTf (2.0 equiv) and 2,4,6-collidine (3.0 equiv),1b along with
R1O-SiEt3 (1.0 equiv). TESOTf (1.0 equiv) and 2,4,6-collidine
(2.0 equiv) cannot complete the preparation of C, probably
because the amount of 2,4,6-collidine reacts with TESOTf. The
formation of 1-(triethylsilyl)collidinium triflate D was confirmed
by MS study. Anyway, more than 1.0 equiv of 2,4,6-collidine
exists so that the reaction system remains weakly basic. In the
next step, the addition of the alcohol (1.5 equiv) to the reaction
mixture afforded the mixed acetal B in high yield. In this
process, the collidinium triflate E (1.5 equiv) should be released.
However, more than 1.0 equiv of 2,4,6-collidine has existed
since the reaction started; therefore, the reaction system is still
kept weakly basic. This is the reason why (1) acid-labile
functional groups were tolerated under this conditions, and (2)
the reversible reaction of mixed acetal B to raw material A or
overreaction of B to symmetrical acetal F did not occur (Scheme
4). These advantages clearly overcome troublesome problems
of traditional mixed acetal formations.
Since the optimized conditions for supplying the O,S- and
N,O-acetals were in hand, they were applied to various acetals
(Table 5). The cyclic acetal, dioxolane (entry 1), and dimethyl
acetal having a secondary carbon (entry 2) gave the desired O,S-
(7) For O,S-acetals, see: (a) Mandai, T.; Hara, K.; Nakajima, T.; Kawada,
M.; Otera, J. Tetrahedron Lett. 1983, 24, 4993-4996. (b) Sato, T.; Okura,
S.; Otera, J.; Nozaki, H. Tetrahedron Lett. 1987, 28, 6299-6302. (c) Sato,
T.; Kobayashi, T.; Gojo, T.; Yoshida, E.; Otera, J.; Nozaki, H. Chem. Lett.
1987, 1661-1664. (d) Sasaki, M.; Noguchi, T.; Tachibana, K. J. Org. Chem.
2002, 67, 3301-3310 and references cited therein. For N,O-acetals, see:
(e) Hassner, A.; Fibriger, R.; Amarasekara, A. S. J. Org. Chem. 1988, 53,
22-27. (f) Yanai, H.; Taguchi, T. Tetrahedron Lett. 2005, 46, 8639-8643.
(8) For selected examples on O,S-acetal formation, see: Miura, T.;
Masaki, Y. Tetrahedron 1995, 51, 10477-10486 and refs 2 and 7a,b.
(9) For selected examples on N,O-acetal formation, see: (a) Kirchmeyer,
S.; Mertens, A.; Olah, G. A. Synthesis 1983, 500-502. (b) Kim, S.; Park,
J. H.; Lee, S. Tetrahedron Lett. 1989, 30, 6697-6700. (c) Kim, S.; Do, J.
Y.; Kim, S. H.; Kim, D. J. Chem. Soc., Perkin Trans. 1 1994, 2357-2358.
(10) N-Nucleophiles such as benzyl amine and aniline were also tried.
Although collidinium salt from acetal 1a was consumed, desired N,O-acetals
could not be isolated probably due to their stabilities. The introduction of
other N-nucleophiles except azide is on progress.
Efficient Formation of O,S-Acetals and N,O-Acetals: O,S-
Acetals and N,O-acetals are also useful as protective groups of
carbonyl functions2a as well as versatile units in synthetic organic
7900 J. Org. Chem., Vol. 72, No. 21, 2007

Organic Chemistry Using Weakly Electrophilic Salts
TABLE 4. Reaction of Acetal 1a with NaN3 or TMSN3
TABLE 6. Chemoselectivity of the Reactions
time
(h)
yield
(%)
entry
nucleophile
additivea
none
18-crown-6
none
CsF
TBAT
1
2
3
4
5
NaN3 (3.0 equiv)
NaN3 (1.5 equiv)
TMSN3 (1.2 equiv)
TMSN3 (1.2 equiv)
TMSN3 (1.2 equiv)
12
1.5
20
16
1.5
trace
97
time
(min)
yield
(%)
entry
nucleophile
product
0b
1
2
3
allylOH
PhSLia
30
5
10
3iB (Nu ) OAllyl)
7iE (Nu ) SPh)
8iA (Nu ) N3)
70
72
73
39b
77
b
NaN3
a Same molar additive as that of nucleophile was added. b 49% of enol
a 1.0 M in THF solution was used. b 18-Crown-6 (3.0 equiv) was added
as additive.
ether A was obtained together in each entry.
acetals in high yields. The reaction proceeds under weakly basic
conditions. Therefore, no overreaction occurs, and many acid-
labile functional groups can remain intact. The chemoselectivity
of the reaction is very high, and only acetals can react under
the stated conditions. The introduction of other nucleophiles to
the collidinium salt intermediates and their applications are now
in progress.
TABLE 5. Reactions of Various Acetals with S- or N-Nucleophile
Experimental Section
General Procedure for the Synthesis of O,O-Mixed Acetals.
2,4,6-Collidine (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 disappearance of an acetal on 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 saturated aqueous NaHCO3 and extracted with CH2-
Cl2. The organic layer was dried over Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by column chro-
matography using neutralized SiO2 (purchased from Kanto Chemi-
cal) to give an O,O-mixed acetal.
a 1.0 M in THF solution (3.0 equiv) was added. Reaction time was 5
min in each entry. b NaN3 (1.5 equiv) and 18-crown-6 (1.5 equiv) were
added. Reaction time was 30 min in each entry.
Entry 3 in Table 1: 2aC (31.0 mg, 94%) was obtained from 1a
(29.6 mg, 0.146 mmol), TESOTf (66 µL, 0.293 mmol), 2,4,6-
collidine (58 µL, 0.439 mmol), and propargyl alcohol (13 µL, 0.219
mmol). Eluent: hexane/Et2O ) 40/1. 2aC: colorless oil; IR (KBr)
3310, 1117, 1049 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.86 (3H,
t, J ) 6.6 Hz), 1.13-1.40 (14H, m), 1.56-1.64 (2H, m), 2.38 (1H,
t, J ) 2.5 Hz), 3.30 (3H, s), 4.18 (2H, d, J ) 2.5 Hz), 4.58 (1H,
t, J ) 5.8 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.7, 24.5,
29.3, 29.4, 29.49, 29.50, 31.9, 32.6, 52.4, 52.8, 73.8, 79.9, 102.7.
Anal. Calcd for C14H26O2: C, 74.29; H, 11.58. Found: C, 74.54;
H, 11.55.
and N,O-acetals in good yields. Various functional groups, such
as methyl ether, acetate ester, TBS ether, and trityl ether, were
also intact under the stated conditions (entries 3-6). It is
noteworthy that acid-labile protective groups, such as TBS ether
and trityl ether, were not affected because the reactions
proceeded under weakly basic conditions.
Chemoselectivity of the Reaction: Finally, we examined the
chemoselectivity of our method. As a substrate, we chose
compound 1i that included the acetal and ketal functions in the
same molecule. As shown in Table 6, in every reaction, the
compounds, which are selectively reacted at the acetal, and not
the ketal, were obtained in fairly good yields. No products
formed by the reaction at the ketal function were observed. The
reactions proceed via 2,4,6-collidinium salt intermediates as
shown above, and we already have proved the chemoselective
formation of the intermediates from the substrates having the
acetal and ketal functions in the same molecule (for chemose-
lective formation of the 2,4,6-collidinium salt intermediates, see
refs 1a,b and 3). Then, these results show the high chemose-
lectivity of our method.
Entry 1 in Table 6: 3iB (40.4 mg, 70%) was obtained from 1i
(32.8 mg, 0.144 mmol), TESOTf (65 µL, 0.288 mmol), 2,4,6-
collidine (57 µL, 0.432 mmol), and allyl alcohol (29 µL, 0.432
mmol). Eluent: CH
2Cl2/AcOEt ) 20/1. 3iB: colorless oil; IR (KBr)
1
1647, 1107, 912 cm-1; H NMR (300 MHz, CDCl3) δ 0.61 (6H,
q, J ) 7.9 Hz), 0.96 (9H, t, J ) 7.9 Hz), 1.19-1.33 (2H, m), 1.43-
1.60 (5H, m), 1.71-1.75 (4H, m), 3.50-3.65 (2H, m), 3.75 (2H,
t, J ) 5.3 Hz), 3.93 (4H, s), 4.01 (1H, dd, J ) 5.4, 12.9 Hz), 4.12
(1H, dd, J ) 5.4, 12.9 Hz), 4.70 (1H, t, J ) 5.7 Hz), 5.16 (1H, d,
J ) 10.2 Hz), 5.28 (1H, d, J ) 17.0 Hz), 5.85-5.98 (1H, m); 13
C
NMR (75 MHz, CDCl3) δ 4.4, 6.7, 30.27, 30.30, 32.4, 34.37, 34.39,
39.5, 62.2, 64.16, 64.19, 66.1, 66.2 101.0, 108.9, 116.6, 134.8. Anal.
Calcd for C21H40O5Si: C, 62.96; H, 10.06. Found: C, 63.05; H,
10.00.
General Procedure for the Synthesis of O,S-Acetals. 2,4,6-
Collidine (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
Conclusion
We have developed an efficient method for preparing O,O-
mixed acetals, O,S-acetals, and N,O-acetals from O,O-symmetric
J. Org. Chem, Vol. 72, No. 21, 2007 7901

Fujioka et al.
for the disappearance of an acetal on TLC, a thiol or PhSLi (1.0 M
solution in THF) (1.5-3.0 equiv) was added to the resulting mixture
and stirred at rt. Disappearance of the polar component was
ascertained by TLC. Workup and purification were the same as
that of the O,O-mixed acetal procedure to give an O,S-acetal.
Entry 6 in Table 3: 7aE8a (40.1 mg, quant) was obtained from
1a (29.0 mg, 0.143 mmol), TESOTf (65 µL, 0.286 mmol), 2,4,6-
collidine (57 µL, 0.429 mmol), and PhSLi (1.0 M in THF, 0.43
mL, 0.429 mmol). Eluent: hexane/AcOEt ) 75/1.
Entry 2 in Table 6: 7iE (53.4 mg, 72%) was obtained from 1i
(37.5 mg, 0.164 mmol), TESOTf (74 µL, 0.328 mmol), 2,4,6-
collidine (65 µL, 0.492 mmol), and PhSLi (1.0 M in THF, 0.49
mL, 0.492 mmol). Eluent: hexane/AcOEt ) 15/1. 7iE: colorless
oil; IR (KBr) 1103, 912 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.61
(6H, q, J ) 7.9 Hz), 0.96 (9H, t, J ) 7.9 Hz), 1.14-1.31 (2H, m),
1.45-1.78 (9H, m), 3.53-3.60 (1H, m), 3.79 (2H, t, J ) 5.1 Hz),
3.93 (4H, s), 3.90-4.00 (1H, m), 4.87 (1H, dd, J ) 5.3, 8.0 Hz),
7.26-7.31 (3H, m), 7.47-7.50 (2H, m); 13C NMR (75 MHz,
CDCl3) δ 4.4, 6.7, 29.6, 30.2, 33.2, 34.3, 42.2, 62.0, 64.2, 69.1,
87.5, 108.9, 127.4, 128.6, 133.2, 133.5. Anal. Calcd for C24H40O4-
SSi: C, 63.67; H, 8.91; S, 7.08. Found: C, 63.89; H, 8.93; S, 6.95.
General Procedure for the Synthesis of N,O-Acetals. 2,4,6-
Collidine (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 disappearance of an acetal on TLC, NaN3 (1.5 equiv) and
18-crown-6 (1.5 equiv) were added to the resulting mixture and
stirred at rt. Disappearance of the polar component was ascertained
by TLC. Workup and purification were the same as that of the
O,O-mixed acetal procedure to give an N,O-acetal.
18-crown-6 (70.6 mg, 0.267 mmol). Eluent: hexane/Et2O ) 50/1.
8aA: colorless oil; IR (KBr) 2106, 1103 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.88 (3H, t, J ) 6.7 Hz), 1.27-1.40 (14H, m), 1.72 (2H,
quint, J ) 6.4 Hz), 3.47 (3H, s), 4.27 (1H, t, J ) 6.0 Hz); 13C
NMR (75 MHz, CDCl3) δ 14.1, 22.7, 24.7, 29.18, 29.26, 29.45,
31.9, 34.4, 56.5, 94.3. Anal. Calcd for C11H23N3O: C, 61.93; H,
10.87; N, 19.70. Found: C, 61.93; H, 10.77; S, 19.36.
Entry 3 in Table 6: 8iA (44.7 mg, 73%) was obtained from 1i
(36.1 mg, 0.158 mmol), TESOTf (72 µL, 0.316 mmol), 2,4,6-
collidine (63 µL, 0.474 mmol), NaN3 (30.8 mg, 0.474 mmol), and
18-crown-6 (125 mg, 0.474 mmol). Eluent: CH2Cl2/AcOEt ) 50/
1
1. 8iA: colorless oil; IR (KBr) 2106, 1105, 912 cm-1; H NMR
(300 MHz, CDCl3) δ 0.61 (6H, q, J ) 7.9 Hz), 0.96 (9H, t, J )
7.9 Hz), 1.22-1.34 (2H, m), 1.49-1.76 (9H, m), 3.56-3.65 (1H,
m), 3.78-3.86 (3H, m), 3.94 (4H, s), 4.50 (1H, t, J ) 6.2 Hz); 13
C
NMR (75 MHz, CDCl3) δ 4.3, 6.7, 29.9, 30.2, 32.4, 34.3, 40.6,
62.0, 64.2, 70.3, 91.4, 108.7. Anal. Calcd for C18H35N3O4Si: C,
56.07; H, 9.15; N, 10.90. Found: C, 56.20; H, 9.03; N, 10.75.
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, and
the Shorai Foundation for Science and Technology.
Supporting Information Available: Full experimental details
including the detailed spectroscopic data of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Entry 2 in Table 4: 8aA (36.7 mg, 97%) was obtained from 1a
(36.0 mg, 0.178 mmol), TESOTf (81 µL, 0.356 mmol), 2,4,6-
collidine (71 µL, 0.534 mmol), NaN3 (17.4 mg, 0.267 mmol), and
JO071187G
7902 J. Org. Chem., Vol. 72, No. 21, 2007