Mild deprotection of methylene acetals in combination with trimethylsilyl triflate-2,2′-bipyridyl

Article abstract of DOI:10.1248/cpb.58.426

The facile deprotection of methylene acetal protection of diols under mild conditions is established. The combination of trimethylsilyl triflate (TMSOTf) and 2,2′-bipyridyl followed by a weakly acidic hydrolysis was effective and the substrates having acid sensitive functional groups can be tolerated under the stated conditions. The selective deprotection between methylene acetal and benzophenone ketal was achieved.

Full text of DOI:10.1248/cpb.58.426

426
Notes
Chem. Pharm. Bull. 58(3) 426—428 (2010)
Vol. 58, No. 3
Mild Deprotection of Methylene Acetals in Combination with
ꢀ
Trimethylsilyl Triflate–2,2 -Bipyridyl
Hiromichi FUJIOKA,* Kento SENAMI, Ozora KUBO, Kenzo YAHATA, Yutaka MINAMITSUJI, and
Tomohiro MAEGAWA
Graduate School of Pharmaceutical Sciences, Osaka University; 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan.
Received November 11, 2009; accepted December 15, 2009; published online December 17, 2009
The facile deprotection of methylene acetal protection of diols under mild conditions is established. The
combination of trimethylsilyl triflate (TMSOTf) and 2,2ꢀ-bipyridyl followed by a weakly acidic hydrolysis was ef-
fective and the substrates having acid sensitive functional groups can be tolerated under the stated conditions.
The selective deprotection between methylene acetal and benzophenone ketal was achieved.
Key words deprotection; methylene acetal; diol; 2,2ꢀ-bipyridyl; pyridinium intermediate
The protection of functional groups is essential for organic tions has been accomplished (Chart 2).19) Different types of
syntheses. The choice of the appropriate protective group is protected diols, such as the more hindered hydroxy group
important for the total synthesis of complex molecules and a protected diol and less hindered one, can be obtained by a
number of protective groups for various functional groups one-pot procedure.
have been developed to date.1,2) The diol is a basic structure
During this study, we found that it is important for the syn-
of polyhydroxy molecules and many protective groups for it theses of different types of protected diols to modify the suc-
have been developed.1,2) Dioxolanes and dioxanes are com- cessive treatment of the pyridinium intermediate generated in
mon protective groups for diols, especially, isopropylidene the reaction. During an initial attempt for the deprotection of
ketal is the most common protective group which can be tol- methylene acetal, the hydrolysis of the pyridinium intermedi-
erated under strong basic conditions and cleaved under ate of 4-octyl-1,3-dioxolane (1a) with H2O (neutral condi-
weakly acidic conditions. Other dioxolanes and dioxanes are tions) gave a mixture of the free diol (2a) and mono-silylated
also used, but some of them, which are prepared from diols diol (3) (Table 1, entry 1). Further investigation of the hy-
and aldehydes, such as benzylidene acetal, generate a new
stereogenic center which affords a diastereo mixture and may
cause complex handling, separation and NMR analysis con-
cerns. To prevent these problems, the cyclic carbonates or
boronates are employed for the diol protection although the
deprotection of carbonates requires strong basic conditions,
while the less steric hindered boronates are unstable toward
Chart 1. Mild Deprotection of THP Ether or MOM Ether in the Combina-
tion of the TESOTf–Pyridine Derivatives
hydrolysis.1,2)
The methylene acetal function is one of the protective
groups for the 1,2- or 1,3-diols and its dioxolanes or diox-
anes form a single isomer. However, the difficulty of depro-
tection of the methylene acetal is a common recognition and
there are significant issues in its use. Because strong acidic
conditions or harsh reaction conditions are required to cleave
the methylene acetals,3—15) the methylene acetal function is
rarely used for the protection of diols.1,2) Therefore, the de-
velopment of a mild and convenient deprotection method
would open up the utility of methylene acetal and provide a
novel alternative for the diol protection because it tolerates
not only basic conditions, but also mild acidic conditions. We
now describe the facile deprotection of methylene acetal
under mild conditions in combination with trimethylsilyl tri-
flate (TMSOTf) and 2,2ꢀ-bipyridyl.
Chart 2. Regiocontrolled Protection of Diols from Methylene Acetals
Table 1. The Effect of Hydrolysis Conditions
Yield (%)
Entry
Conditions
Time (h)
2a
3
We have reported that the facile deprotection of THP
ethers16,17) as well as MOM ethers18) using the combination
of TESOTf–2,4,6-collidine or 2,2ꢀ-bipyridyl via a pyridinium
intermediate (Chart 1). A slightly excess amount of 2,2ꢀ-
bipyridyl was used over Lewis acid in this reaction, which
made the reaction conditions mild, and an acid-labile func-
tion can be tolerated under these conditions.
1
2
3
H2O
Sat. K2CO3 aq.
1 N HCl
1 N HCl
1 N HCl
5
12
2
1.5
24
24
54
0
40
90
Trace
0
78
83
13
4a)
5b)
6c)
Trace
d)
d)
1 N HCl
—
—
a) TMSOTf was used instead of TESOTf. b) The reaction was performed in the ab-
sence of 2,2ꢀ-bipyridyl. c) The reaction was performed in the absence of TESOTf and
Further development of this method, the regiocontrolled
protection of diols from methylene acetals under mild condi- 2,2ꢀ-bipyridyl. d) No reaction.
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: fujioka@phs.osaka-u.ac.jp

March 2010
427
Table 2. Mild Deprotection of Methylene Acetals of 1,2- and 1,3-Diols in
drolysis conditions revealed that the treatment with saturated
K2CO3 aq. (basic conditions) only afforded 3 (entry 2), but
the treatment with 1 N HCl (weakly acidic conditions) gave
2a in good yield as a single product (entry 3). The use of
TMSOTf instead of TESOTf improved the yield of 2a up to
83% (entry 4). The reaction of 1a with TESOTf only af-
forded 2a, but in low yield (13%), and the formation of the
pyridinium intermediate is important for the efficient depro-
tection (entry 5). The deprotection did not proceed without
TESOTf and 2,2ꢀ-bipyridyl (entry 6). The hydrolysis was
promoted by 2,2ꢀ-bipyridyl which may help H2O access to
the cationic acetal carbon in the pyridinium intermediate.18)
We applied the optimized conditions to various methylene
acetals of the 1,2-diols and 1,3-diol. The formations of the
pyridinium salts were complete within 2.5 h in each substrate
and the hydrolysis of the intermediates gave the correspond-
ing diols 2 in good to high yields (Table 2). A variety of
functional groups, such as benzyl, benzoyl and TBS, were
tolerated under these conditions (entries 3—5). It should be
noted that the trityl group, an acid-labile functional group,
survived under these conditions (entry 6). The methylene ac-
etals of the inner 1,2-diols were also deprotected within 1.5 h
(entries 8 and 9). 1,3-Dioxane was also converted to a 1,3-
diol under the same conditions (entry 10). However, the
methylene acetal of catechol did not form any pyridinium
salt and no deprotected product was observed (entry 11).
The chemoselective deprotection between methylene ac-
etal and benzophenone ketal within the same molecule was
also examined. It is known that benzophenone ketal is depro-
tected by a weak acid such as AcOH or a diluted HCl solu-
tion.1,2) The key to the selective deprotection by our method
is dependent on the steric environment in which the Lewis
acid coordinates the less hindered oxygen with discrimina-
tion. Consequently, the selective deprotection of methylene
acetal in 4 proceeded under the conditions affording the diol
5 with the benzophenone ketal intact (Chart 3).
Combination of TMSOTf–2,2ꢀ-Bipyridyl
Time (x/y)
(h)
Yield
(%)
Entry
1
Substrate
Product
0.3/1.5
83
1a
1b
2a
2b
2
3
2.5/1
0.5/3
82
72
(RꢁBn) 1c
(RꢁBz) 1d
(RꢁTBS) 1e
(RꢁTr) 1f
2c
2d
2e
2f
4
0.5/3
0.5/6.5
1/4.5
0.3/1
75
72
86
95
5a)
6
7b)
1g
2g
8b,c)
1.5/1.5
56
1h
1i
2h
2i
9
0.5/0.5
2/1.5
—
86
84
10b,c)
In conclusion, the facile and mild deprotection of methyl-
ene acetals using TMSOTf and 2,2ꢀ-bipyridyl has been de-
veloped. The weakly acidic hydrolysis promoted the depro-
tection of methylene acetals to afford the free diols in good
to high yields. The present method is so mild that various
functional groups including the trityl group can be tolerated
under the established conditions. This method is also appli-
cable to the selective deprotection of methylene acetal in the
presence of benzophenone ketal.
1j
2j
11
—
N. R.d)
1k
a) Sat. NH4Cl aq. was used instead of 1 N HCl. b) 4.0 eq of TMSOTf and 6.0 eq of
2,2ꢀ-bipyridyl were used. c) The reaction with TMSOTf and 2,2ꢀ-bipyridyl was con-
ducted at rt. d) No reaction.
Experimental
General Procedure. n-Decane-1,2-diol (2a)20) (Table 1, Entry 4)
TMSOTf (73.2 ml, 0.405 mmol) was added to a solution of methylene
acetal 1a (37.3 mg, 0.202 mmol) and 2,2ꢀ-bipyridyl (94.8 mg, 0.607 mmol)
in CH2Cl2 (0.4 ml) at 0 °C under N2. The reaction mixture was stirred for
30 min at 0 °C. After disappearance of 1a on TLC, Et2O (2 ml) and 1 N HCl
(2 ml) was added to the reaction mixture. The resulting solution was stirred
until disappearance of the pyridinium salt (highly polar compound). The
mixture was extracted with CH2Cl2 (or AcOEt). The combined organic layer
was washed with saturated NaHCO3 aq. then dried over Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by flash SiO2 column chro-
matography (hexanes/AcOEtꢁ1/1) to give a diol 2a (29.1 mg, 83%).
4-Phenylbutane-1,2-diol (2b)21) (Table 2, Entry 2) According to the
general procedure, the treatment of 1b (34.6 mg, 0.194 mmol) with 2,2ꢀ-
bipyridyl (90.9 mg, 0.582 mmol) and TMSOTf (70.0 ml, 0.387 mmol), then
treatment of Et2O (2 ml) and 1 N HCl (2 ml) for 1 h gave 2b (26.6 mg, 82%).
Eluent; hexanes/AcOEt (2/1) to hexanes/AcOEt (1/1).
Chart 3. Selective Deprotection of Methylene Acetal in the Presence of
Benzophenone Ketal
2,2ꢀ-bipyridyl (93.3 mg, 0.597 mmol) and TMSOTf (72.0 ml, 0.398 mmol),
then treatment of Et2O (2 ml) and 1 N HCl (2 ml) for 3 h gave 2c (42.3 mg,
72%). Eluent; hexanes/AcOEt (1/1) to AcOEt.
11-Benzoyloxy-undecane-1,2-diol (2d) (Table 2, Entry 4) According
to the general procedure, the treatment of 1d (63.4 mg, 0.199 mmol) with
2,2ꢀ-bipyridyl (93.3 mg, 0.597 mmol) and TMSOTf (72.0 ml, 0.398 mmol),
then treatment of Et2O (2 ml) and 1 N HCl (2 ml) for 3 h gave 2d (46.1 mg,
75%). Eluent; hexanes/AcOEt (1/1) to AcOEt. White solid. 1H-NMR
(400 MHz, CDCl3) d: 1.30—1.80 (16H, m), 2.61—2.65 (2H, m), 3.43—3.45
(1H, m), 3.63—3.69 (2H, m), 4.31 (2H, t, Jꢁ6.4 Hz), 7.42—7.46 (2H, m),
7.54—7.57 (1H, m), 8.03—8.05 (2H, m); 13C-NMR (126 MHz, CDCl3) d:
11-Benzyloxy-undecane-1,2-diol (2c)22) (Table 2, Entry 3) According
to the general procedure, the treatment of 1c (61.0 mg, 0.199 mmol) with

428
Vol. 58, No. 3
3.42 (1H, m), 3.61—3.69 (3H, m), 4.08—4.16 (2H, m), 7.24—7.34 (6H, m),
7.48—7.52 (4H, m); 13C-NMR (126 MHz, CDCl3) d: 25.5, 25.7, 29.4, 29.5
(2ꢂC), 33.1, 33.4, 66.8, 70.0, 72.3, 76.8, 109.3, 126.2, 127.8, 127.9, 128.1,
142.8; HR-MS (EI) Calcd for C25H34O4 (Mꢃ) 398.2452, Found 398.2457.
25.4, 25.9, 28.6, 29.2, 29.4 (3ꢂC), 29.5, 33.1, 65.1, 66.8, 72.3, 128.3, 129.5,
130.5, 132.8, 166.7; HR-MS (FAB) Calcd for C18H29O4 (MꢃꢃH) 309.2066,
Found 309.2050.
11-tert-Butyldimethylsilyloxy-undecane-1,2-diol (2e) (Table 2, Entry
5) According to the general procedure, the treatment of 1e (66.4 mg,
0.201 mmol) with 2,2ꢀ-bipyridyl (94.8 mg, 0.607 mmol) and TMSOTf
(73.1 ml, 0.404 mmol), then treatment of Et2O (2 ml) and saturated NH4Cl
aq. (2 ml) for 6.5 h gave 2e (46.2 mg, 72%). Eluent; hexanes/AcOEt (1/1) to
AcOEt. White solid. 1H-NMR (500 MHz, CDCl3) d: 0.00 (6H, s), 0.85 (9H,
s), 1.23—1.46 (16H, m), 2.41 (2H, s), 3.36—3.40 (1H, m), 3.53—3.65 (4H,
m); 13C-NMR (126 MHz, CDCl3) d: ꢄ5.3, 18.4, 25.5, 25.8, 26.0, 29.4, 29.5
(2ꢂC), 29.6, 32.8, 33.1, 63.3, 66.8, 72.3; HR-MS (FAB) Calcd for
C17H39O3Si (MꢃꢃH) 319.2668, Found 319.2669.
11-Triphenylmethyloxy-undecane-1,2-diol (2f) (Table 2, Entry 6)
According to the general procedure, the treatment of 1f (92.5 mg,
0.202 mmol) with 2,2ꢀ-bipyridyl (94.8 mg, 0.607 mmol) and TMSOTf
(73.1 ml, 0.404 mmol), then treatment of Et2O (2 ml) and 1 N HCl (2 ml) for
4.5 h gave 2f (77.5 mg, 86%). Eluent; hexanes/AcOEt (1/1). White solid. 1H-
NMR (500 MHz, CDCl3) d: 1.26—1.42 (16H, m), 1.58—1.66 (2H, m), 2.04
(1H, br s), 2.14 (1H, br s), 3.03 (2H, t, Jꢁ6.7 Hz), 3.40—3.44 (1H, m),
3.63—3.70 (2H, m), 7.20—7.45 (15H, m); 13C-NMR (126 MHz, CDCl3) d:
25.5, 26.4, 29.5, 29.6, 30.0, 33.2, 63.7, 66.8, 72.3, 86.2, 126.8, 127.7, 128.7,
144.5; HR-MS (FAB) Calcd for C30H38O3Na (MꢃꢃNa) 469.2719, Found
469.2724.
Acknowledgment This work was supported by a Grant-in-Aid for Sci-
entific Research (B) and for Scientific Research for Exploratory Research
from Japan Society for the Promotion of Science (JSPS) and Special Coordi-
nation Funds for Promoting Science and Technology of the Ministry of Edu-
cation, Culture, Science and Technology, the Japanese Government.
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