Selective Monoacetylation of Unsymmetrical Diols Catalyzed by Silica Gel-Supported Sodium Hydrogen Sulfate

Full text of DOI:10.1021/jo971367y

8952
J . Org. Chem. 1997, 62, 8952-8954
Selective Mon oa cetyla tion of
Un sym m etr ica l Diols Ca ta lyzed by Silica
Gel-Su p p or ted Sod iu m Hyd r ogen Su lfa te
Gary W. Breton*
Department of Chemistry, Berry College, P.O. Box 495016,
Mount Berry, Georgia 30149-5016
Received J uly 24, 1997
Selective monoacetylation of unsymmetrical diols is an
important procedure in organic synthesis as is reflected
by the number of methods that have been developed to
effect this transformation.1,2 Acetylation via the process
of transesterification employing heterogeneous catalysts
is of particular convenience since starting esters (e.g.,
ethyl acetate) are readily available and the catalyst may
be easily separated from the product mixture through
simple filtration.1c,3,4 High selectivity for acetylation of
primary hydroxyl group sites in the presence of secondary
sites has been previously reported with the use of
alumina as catalyst.1c,3 This method suffers, however,
from the large amounts of catalyst required (10 g of Al2O3/
mmol of diol) as well as relatively high reaction temper-
atures (75-80 °C).
F igu r e 1. Plots of yield vs time for the NaHSO4‚SiO2-
catalyzed acetylation of 1 in a 30% solution of ethyl acetate in
hexane at 50 °C: diol 1 (+), monoester 2 (b), and diester 4
(9). Monoester 3 is not shown in the figure for purposes of
clarity; however, a maximum yield of 4% at 9 h was observed.
Ta ble 1. Acetyla tion of Diol 1a
% yield
reaction conditions
2
3
4
ratio 2:3
We were attracted to a heterogeneous silica gel-
supported NaHSO4 catalyst (NaHSO4‚SiO2) that has been
reported to readily acetylate simple alcohols via trans-
esterification from EtOAc and also to selectively mono-
acetylate symmetrical diols.4 Small amounts of catalyst
(57 mg/mmol of diol) at reasonable temperatures (60 °C)
effectively catalyzed the transesterification process. To
our knowledge no attempt has been made to employ this
catalyst for the esterification of unsymmetrical diols.5
Herein we report our findings that NaHSO4‚SiO2 is an
excellent catalyst for the selective acetylation of unsym-
metrical diols.
NaHSO4‚SiO2, EtOAc/hexane,
50 °C, 9 h
Ac2O (1 equiv), pyridine,
CH2Cl2, 25 °C, 24 h
AcCl (1 equiv), CH2Cl2,
25 °C, 24 h
71b
4
12
95:5
59
4
9
3
10
94:6
79:21
96:4
34
27
NaHSO4, EtOAc/hexane,
50 °C, 8 h
65c
20b
a
Yields determined by GC analysis of the crude reaction
mixtures. Values represent the average of at least three runs
b
which agreed within (1% unless otherwise specified. Values of
several runs agreed within (2%. c Significant amounts of several
unidentified volatile byproducts were observed in the GC analysis
of the crude reaction mixture (see ref 6).
Upon warming a solution of 1 mmol of 1,5-hexanediol
(1; eq 1) in 15 mL of a 30% solution of ethyl acetate in
hexane in the presence of NaHSO4‚SiO2 (100 mg, 3.0
mmol NaHSO4/g) for 9 h followed by filtration, primary
monoacetate 2 was afforded in 71% yield (Table 1). Only
4% of the secondary isomer 3 was formed under these
conditions (ratio of 2:3 ) 95:5). Some of the bisacetate 4
was also formed (12% yield). Figure 1 shows the progress
of the reaction as a function of time. The yield of 2 was
greatest at approximately 9 h, at which time the yield of
4 became significant. Reaction beyond this point was
characterized by slow conversion of 2 to 4. Selectivity
for monoacetate 2 relative to 3 increased from 90:10 at 1
h to 95:5 at 9 h and finally to 97:3 at 10 h, after which it
remained constant up to 14 h. A reaction temperature
of 50 °C proved to be optimal for the reaction: higher
temperatures (e.g., 65 °C) afforded lower yields of 2 (59%
at 8 h), while lower temperatures (25 °C) resulted in
impractically long reaction times. Results were repro-
ducible within a few percent using the same catalyst over
several months as well as with different batches of
catalyst prepared in the same manner (see the Experi-
mental Section).
(1) (a) Zhu, P. C.; Lin, J .; Pittman, C. U. J . Org. Chem. 1995, 60,
5729-5731. (b) Bianco, A.; Brufani, M.; Melchioni, C.; Romagnoli, P.
Tetrahedron Lett. 1997, 38, 651-652. (c) Rana, S. S.; Barlow, J . J .;
Matta, K. L. Tetrahedron Lett. 1981, 22, 5007-5010. (d) Yamada, S.;
Sugaki, T.; Matsuzaki, K. J . Org. Chem. 1996, 61, 5932-5938. (e)
Nagao, Y.; Fujita, E.; Kohno, T.; Yagi, M. Chem. Pharm. Bull. 1981,
29, 3202-3207.
(2) Protective Groups in Organic Synthesis; Greene, T. W., Wuts, P.
G. M., Eds.; Wiley: New York, 1991; pp 88-92.
(3) Posner, G. H.; Oda, M. Tetrahedron Lett. 1981, 22, 5003-5006.
(4) (a) Nishiguchi, T.; Kawamine, K.; Ohtsuka, T. J . Org. Chem.
1992, 57, 312-316. (b) Nishiguchi, T.; Taya, H. J . Chem. Soc., Perkin
Trans. 1 1990, 172-173.
(5) Nishiguchi reported that attempted acetylation of symmetrical
secondary diols resulted in the formation of substantial quantities of
olefins along with the expected esters as a result of competing acid-
catalyzed dehydration (ref 4). We speculate, therefore, that the reason
the acetylation of unsymmetrical diols containing secondary sites was
not investigated was the anticipation that they would similarly undergo
dehydration.
The results obtained for acetylation over NaHSO4‚SiO2
may be compared to those obtained using more conven-
tional acetylating agents such as (1) Ac2O, pyridine, (2)
AcCl, and (3) transesterification over unsupported NaH-
SO4 (Table 1). In all cases, lower yields and/or poorer
selectivities were observed.6 Furthermore, the use of
S0022-3263(97)01367-4 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 25, 1997 8953
Ta ble 2. Na HSO4‚SiO2-Ca ta lyzed Acetyla tion of
Ta ble 3. Selective Acetyla tion of Sa tu r a ted Hyd r oxyl
Gr ou p sa ,b
Un sym m etr ica l Diolsa ,b
a
Isolated yields. b Conducted according to the general procedure
described in the Experimental Section, but at a reaction temper-
ature of 67 °C and for the following reaction times: 10, 6 h; 11,
18 h; 12, 72 h.
a
b
Isolated yields. Reaction conducted according to the general
procedure described in the Experimental Section. c Ratio deter-
mined by gas chromatographic analysis of a mixture of isolated
Selective acetylation of aliphatic hydroxyl groups in the
presence of phenolic hydroxyl groups was achieved and
in good yields (compounds 10-12, Table 3). Further-
more, the saturated secondary hydroxyl group of â-es-
tradiol (12) was acetylated preferentially over the phe-
nolic hydroxyl group. Therefore, a qualitative ranking
of hydroxyl group reactivity toward acetylation under
these conditions of primary > secondary > phenol may
be made.
d
monoacetates. Ratio determined by isolation of individual iso-
mers. e 72 h of reaction time.
NaHSO4‚SiO2 eliminates the need for corrosive reagents
(i.e., Ac2O and AcCl), allows for simple reaction workup
via filtration, and does not require aqueous washings to
remove catalysts or byproducts that characterize the
more conventional methods.
Several acyclic diols were subjected to acetylation
under these reaction conditions, and results similar to
those of diol 1 were obtained (diols 5-8, Table 2). Good
yields of monoacetates and high selectivity for acetylation
at the primary site (typically >95:5 for primary:second-
ary) were observed in each case. The progress of each of
the reactions was followed by thin-layer chromatography,
and the reaction halted (by cooling and filtration from
the catalyst) upon disappearance of starting diol. In most
cases 9 h was a sufficient reaction time. Allowing the
reaction to proceed significantly beyond this point re-
sulted in a decrease in yield of monoacetate and an
increase in yield of the corresponding bisacetate (see
Figure 1).
Acetylation of betulin (9) proceeded under these condi-
tions to afford a 69% yield of the primary monoacetate
although 72 h of reaction time was required. A 14% yield
of the bisacetate was observed in addition to a trace
amount of the secondary monoacetate. The lower reac-
tivity of 9 relative to the acyclic diols may be attributed
to the greater steric bulk encountered by this diol upon
approach toward the surface of the silica gel.
In summary, a convenient and selective method of
acetylation of unsymmetrical diols has been devised. This
method affords greater yields of monoacetate products
and higher selectivity for primary hydroxyl groups over
secondary and phenolic groups than more traditional
methods of acetylation. Lesser amounts of catalyst are
required than previously reported heterogeneous cata-
lysts. Finally, corrosive acetylating reagents are avoided,
and reaction workup is effected through a simple filtra-
tion process.
Exp er im en ta l Section
Gen er a l. All reactions were conducted in oven-dried glass-
ware. Unless otherwise indicated, reagents were obtained from
commercial suppliers and used without further purification.
Column chromatography was conducted on Merck grade 60
(230-400 mesh) silica gel. 1H NMR spectra were recorded in
CDCl3 at 60 MHz. Gas chromatography was conducted on a
Hewlett-Packard 5890 instrument using a 6’ × 1/8” stainless
steel column packed with 10% carbowax 20M on 80/100 Chro-
mosorb W AW at 130 °C. All products were identified by
comparison of their physical and/or spectroscopic data (IR, 1H
NMR) with published data (as for the monoacetates of 9,7 11,8
and 121e) or by comparison with the data of corresponding
materials independently synthesized according to published
procedures [for compound 2, monoacetates of 5-8, and 10, see
refs 2 (acetylation via Ac2O, pyridine) and 3].
(6) Interestingly, unsupported NaHSO4 gave results similar in yield
and selectivity to those of the supported reagent. However, gas
chromatographic analysis of the reaction mixture revealed that upon
attaining the highest yield (65%) of monoacetate 2 (at 8 h of reaction
time) further conversion of 2 to 4 occurred at a much faster rate than
was the case with the supported reagent (thus, a 70% yield of 2 was
observed at 10 h using the supported reagent versus a 55% yield at 10
h over the unsupported reagent). In addition, appreciable amounts of
unidentified volatile byproducts were produced from the reaction which
were detected in only trace amounts using the supported reagent.
(7) Tietze, L. F.; Heinzen, H.; Moyna, P.; Rischer, M.; Neunaber, H.
Liebigs Ann. Chem. 1991, 1245-1249.
P r ep a r a tion of th e Na HSO4‚SiO2 Ca ta lyst. The following
procedure is a modification of Nishiguchi’s method:9 To a
(8) Dictionary of Organic Compounds, 5th ed.; Buckingham, J ., Ed.;
Chapman and Hall: New York, 1982; Fourth Supplement, p 207.
(9) Nishiguchi, T.; Kamio, C. J . Chem. Soc., Perkin Trans. 1 1989,
707-710.

8954 J . Org. Chem., Vol. 62, No. 25, 1997
Notes
solution of 4.14 g (0.03 mol) of NaHSO4‚H2O in 20 mL of water
in a 100-mL beaker containing a stir bar was added 10 g of SiO2
(column chromatographic grade, 60 Å, 200-400 mesh). The
mixture was stirred for 15 min and then gently heated on a hot
plate, with intermittent swirling, until a free-flowing white solid
was obtained. The catalyst was further dried by placing the
beaker in an oven maintained at 120 °C for at least 48 h prior
to use.
by TLC (SiO2 plates, eluting with 3:2 hexane/ethyl acetate,
aqueous phosphomolybdic acid stain) until diol was no longer
apparent (typically 9 h). The mixture was cooled and gravity-
filtered, and the recovered catalyst was washed with CH2Cl2 (50
mL). The combined organics were concentrated on a rotary
evaporator, and the resulting residue was column-chromato-
graphed (SiO2, eluting with 3:2 hexane/ethyl acetate) to afford
pure materials. Deviations from this general procedure are
detailed in the footnotes of the tables.
Gen er a l P r oced u r e for th e Acetyla tion of Diols.
A
solution of 1 mmol of diol was dissolved in 15 mL of a 30%
solution by volume of ethyl acetate in hexane in a 25-mL round-
bottomed flask containing a stir bar. To this solution was added
100 mg of NaHSO4‚SiO2 prepared as described above. The flask
was fitted with a condenser and drying tube, and the mixture
was heated to 50 °C with stirring. The reaction was monitored
Ack n ow led gm en t. This research was supported by
the donors of the Petroleum Research Fund, adminis-
tered by the American Chemical Society.
J O971367Y