Removal of acyl protecting groups using solid NaOH and a phase transfer catalyst

Article abstract of DOI:10.1055/s-2003-39309

Acetyl-, benzoyl- and pivoyl-protected alcohols and phenols undergo smooth deacylation in a two-phase system of powdered NaOH and Bu₄NHSO₄ in THF or CH₂Cl₂.

Full text of DOI:10.1055/s-2003-39309

LETTER
991
Removal of Acyl Protecting Groups Using Solid NaOH and a Phase
Transfer Catalyst
Removal of
Acyl.Protecting
G
D
roups avid Crouch,* Jennifer S. Burger, Karolina A. Zietek, Amy B. Cadwallader, James E. Bedison,
Magda M. Smielewska
Department of Chemistry, Dickinson College, Box 1773, Carlisle, PA 17013-2896, USA
Fax +1(717)2451995; E-mail: crouch@dickinson.edu
Received 24 March 2003
Table 1 Effect of Solvent and Quantity of NaOH on Deacetylationa
Abstract: Acetyl-, benzoyl- and pivoyl-protected alcohols and
phenols undergo smooth deacylation in a two-phase system of
powdered NaOH and Bu4NHSO4 in THF or CH2Cl2.
O
NaOH
TBAH
Ph
O
CH3
THF
Ph
OH
solvent
Key words: protecting groups, alcohols, phase-transfer catalysis,
acyl groups, deprotection
Equiv of NaOH
CH2Cl2
51%
62
3
5
68%
75
As synthetic targets have become increasingly complex,
the importance of protecting groups has grown.1–3 Al-
though silyl ethers have achieved prominence as a means
of protecting alcohols, acyl protecting groups continue to
be widely used and development of new methods for their
removal remains an area of active research.3 Generally,
acetyl-, benzoyl- and pivoyl-protecting groups are re-
moved via alkaline hydrolysis.1,2 A number of uses of hy-
droxide-4–6 and alkoxide-containing reagents6–12 have
been described for deacylation under homogeneous con-
ditions. But, to the best of our knowledge, solid-liquid het-
erogeneous systems have not been pursued despite
possible advantages such as ease of application, simple
workup and inexpensive, relatively safe reagents.13 Dur-
ing our studies on the selective deprotection of silyl-pro-
tected phenols, we discovered that a two-phase system of
solid NaOH in 1,4-dioxane containing a phase transfer
catalyst14 also hydrolyzed acetyl-protected alcohols as
well as methyl esters.15 We have now investigated the
generality of this method for the removal of acyl protect-
ing groups and wish to report our findings.
8
88
76
10
93
89
a Isolated yields are given; all products were spectrally iden-
tical with the authentic alcohol.
products were isolated (Table 2). The reaction is general
for acyl-protected 1° alcohols as well as acetyl- and ben-
zoyl-protected 2° alcohols. It is noteworthy that, after the
usual reaction time of 3 hours, a pivoyl-protected 2° alco-
hol (entry 3c) was largely unreacted with only 7% of
hydrolyzed product being recovered. After 24 hours, how-
ever, a more satisfactory yield was achieved. This result is
being investigated as a possible means of selective depro-
tection.9–11
The stability of silyl-protected alcohols to these condi-
tions is illustrated by the recovery of a TIPS-protected al-
cohol from a deacetylation reaction (entry 6). This result
is in accord with our earlier observation that, under these
reactions conditions, silyl-protected alcohols are stable
while aryl silyl ethers undergo desilylation.15
Desilylation of aryl silyl ethers was best effected using
1,4-dioxane as solvent.15 Hoping to use a more common,
readily-available solvent and to optimize the amount of
NaOH needed, a series of reactions was run in CH2Cl2 or
THF with varying quantities of NaOH (Table 1). Yields of
the isolated alcohol were compared and, although CH2Cl2
was useful, slightly better results were obtained using
THF. Additionally, 10 equivalents of powdered NaOH
provided the highest yields with larger excesses of NaOH
failing to improve yields. No attempt to adjust the amount
of phase transfer catalyst was made.
When subjected to these conditions, acyl-protected phe-
nols produced interesting results. Initial attempts to depro-
tect 4-t-butylphenyl acetate 1a produced modest results.
However, when dry THF was used, the reaction mixture
was purged with argon and the reaction was conducted
under an inert atmosphere, the yield of 4-t-butylphenol 2
was considerably improved (Scheme 1). When open to
the air, deacylation reactions of acyl-protected phenols
produced considerable quantities of brightly-colored
baseline residue. But when air was excluded, little or no
such material formed. Benzoyl- and pivoyl-protecting
groups were also removed to produce 4-t-butylphenol in
good yield (Scheme 1).
With optimized reaction conditions in hand, a series of
acetyl-, benzoyl- and pivoyl-protected alcohols was pre-
pared and subjected to the reaction conditions and the
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,0991,0992,ftx,en;S14302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
The effect of steric hindrance due to neighboring ortho
substitutents was also examined. Although reaction times
of 16–18 hours were required, 2,6-dimethylphenyl acetate

992
R. D. Crouch et al.
LETTER
Table 2 Deprotection of Acyl-Protected Alcoholsa
O
CH3
OH
NaOH, TBAH
THF, r.t.
Entry Substrate
Product/yield
O
O
1
O
3
4
75% (45%)a
O
R
OH
O
CH3
OH
a R = Me
b Ph
c t-Bu
93%
96%
95%
NaOH, TBAH
THF, r.t.
5
6
2
O
OH
83% (13%)a
a reaction occurred open to air
O
R
O
Scheme 2
55%
88%
a R = Me
b Ph
3
O
der an inert atmosphere. THF was distilled from sodium–
benzophenone prior to use.
OH
R
In summary, we have devised a new method for the re-
moval of acetyl-, benzoyl- and some pivoyl-protecting
groups from acyl protected alcohols utilizing a two-phase
system with tetrabutylammonium hydrogen sulfate as
phase transfer catalyst. Furthermore, based on our previ-
ous work,15 this method does not affect alkyl silyl ethers
but does deprotect aryl silyl ethers.
93%
a R = Me
b Ph
c t-Bu
54% (94%)b
7% (63%)b
4
(
)
9
(
92%b
(
)
9
OAc
OAc
OH
5
6
(
)
3
)
3
OH
Acknowledgement
87%
TIPSO
OAc
(
)
3
(
)
3
TIPSO
75%
OH
We wish to thank the Whitaker Foundation for support through a
Whitaker Student-Faculty Research Grant, Dickinson College for a
Dana Summer Internship and the Research and Development Com-
mittee of Dickinson College for sabbatical leave support. We also
acknowledge the helpful comments of one of our reviewers.
a All products were identified with 300 MHz 1H NMR and compared
with authentic alcohol.
b Reaction time was 24 hours.
References
3 and 2,4,6-trimethylphenyl acetate 5 were deprotected
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Tetrahedron Lett. 1995, 36, 2001.
using this method (Scheme 2).
A typical procedure is as follows: The acyl-protected al-
cohol (1 equiv), powdered NaOH (10 equiv), Bu4NHSO4
(0.5 equiv) and THF (5 mL/mmol of substrate) were com-
bined in a round-bottomed flask, purged with argon and
stirred under an inert atmosphere at room temperature.
When TLC indicated the disappearance of starting mate-
rial (typically 3 hours), the mixture was filtered through a
Celite pad (phenol products were filtered through acidic
alumina), washing with Et2O. Evaporation of the solvent
followed by column chromatography yielded the depro-
tected alcohol. Powdered NaOH was prepared by grinding
NaOH pellets with a mortar and pestle in a glovebox un-
O
R
OH
(10) Xu, Y.-C.; Bizuneh, A.; Walker, C. J. J. Org. Chem. 1996,
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(11) Xu, Y.-C.; Bizuneh, A.; Walker, C. J. Tetrahedron Lett.
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(12) Reinhard, B.; Faillard, H. Liebigs Ann. Chem. 1994, 193.
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(14) Illi, V. O. Tetrahedron Lett. 1979, 20, 2431.
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Bevis, D. C. Tetrahedron Lett. 1999, 40, 3133.
NaOH, TBAH
THF, r.t.
O
1
2
a
b
c
R = Ac
t-Bu
Ph
70% (49%)a
82%
76%
a reaction occurred open to air
Scheme 1
Synlett 2003, No. 7, 991–992 ISSN 1234-567-89 © Thieme Stuttgart · New York