Regioselective acetylation of diols and polyols by acetate catalysis: Mechanism and application

Article abstract of DOI:10.1021/jo501343x

We propose a principle for H-bonding activation in acylation of hydroxyl groups, where the acylation is activated by the formation of hydrogen bonds between hydroxyl groups and anions. With the guidance of this principle, we demonstrate a method for the selective acylation of carbohydrates. By this method, diols and polyols are regioselectively acetylated in high yields under mild conditions using catalytic amounts of acetate. In comparison to other methods involving reagents such as organotin, organoboron, organosilicon, organobase, and metal salts, this method is more environmentally friendly, convenient, and efficient and is also associated with higher regioselectivity. We have performed a thorough quantum chemical study to decipher the mechanism, which suggests that acetate first forms a dual H-bond complex with a diol, which enables subsequent monoacylation by acetic anhydride under mild conditions. The regioselectivity appears to originate from the inherent structure of the diols and polyols and their specific interactions with the coordinating acetate catalyst.

Full text of DOI:10.1021/jo501343x

Article
pubs.acs.org/joc
Regioselective Acetylation of Diols and Polyols by Acetate Catalysis:
Mechanism and Application
Bo Ren,† Martin Rahm,*,‡,§ Xiaoling Zhang,† Yixuan Zhou,† and Hai Dong*,†
†Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, School of Chemistry & Chemical
Engineering, Huazhong University of Science & Technology, Luoyu Road 1037, Wuhan 430074, People’s Republic of China
‡Department of Chemistry and Chemical Biology, Cornell University, Baker Laboratory, Ithaca 14853, New York, United States
§Department of Applied Physical Chemistry, KTH-Royal Institute of Technology, Teknikringen 30, 10044 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: We propose a principle for H-bonding activation
in acylation of hydroxyl groups, where the acylation is activated
by the formation of hydrogen bonds between hydroxyl groups
and anions. With the guidance of this principle, we demonstrate
a method for the selective acylation of carbohydrates. By this
method, diols and polyols are regioselectively acetylated in high
yields under mild conditions using catalytic amounts of acetate.
In comparison to other methods involving reagents such as
organotin, organoboron, organosilicon, organobase, and metal
salts, this method is more environmentally friendly, convenient,
and efficient and is also associated with higher regioselectivity.
We have performed a thorough quantum chemical study to decipher the mechanism, which suggests that acetate first forms a
dual H-bond complex with a diol, which enables subsequent monoacylation by acetic anhydride under mild conditions. The
regioselectivity appears to originate from the inherent structure of the diols and polyols and their specific interactions with the
coordinating acetate catalyst.
reagents are associated with lower cost and lower toxicity and
are more easily acquired, this method is not very convenient,
due to the formation of cyclic dioxasilolane- or dioxasilinane-
type intermediates prior to the acetylation. Some other
methods involving heavy-metal salts,21−24 organocatalysis,25−27
and enzymes28−31 also have their respective shortcomings, with
respect to convenience, efficiency, and environmentally
sustainable conditions.
Yoshida et al. may have been the first to rationalize the
regioselectivity observed in base-catalyzed acylation reactions of
polyols to the interplay of hydrogen-bonding interactions
within polyol substrates and carboxylate counterions.32,33
Albert et al. further rationalized the acetylation regioselectivity
by dual H-bonding complexes formed between polyol
substrates and carboxylate counterions.34 Spivey et al.35 and
Kawabata et al.36 have discussed the role of carboxylate ions as
the only relevant base for deprotonating the reacting hydroxy
groups. These studies utilized a highly electrophilic N-
acylpyridinium counterion intermediate as the acyl donor. We
recently reported on the application of H-bonding activation in
a highly regioselective acetylation of diols (Scheme 1).37 On the
basis of our results, it appears that H bonding between hydroxyl
groups and anions can activate acetylation in the absence of a
pyridine catalyst and lead to higher regioselectivities. In our
INTRODUCTION
■
It is a prominent challenge to develop a green, convenient, and
highly efficient regioselective carbohydrate protection method
in synthetic carbohydrate chemistry.1−3 Selectively protected
monosaccharides can act as both value-added intermediates and
building blocks for further use in glycosylation reactions.4,5
Efficient methods using organotin reagents have been widely
employed in the past few decades.6−12 However, the employ-
ment of organotin reagents has recently been limited due to
their potential inherent toxicity.13−15 For this reason, some
methods were developed in which only catalytic amounts of
organotin reagents were used9−12 or in which nontoxic
alternatives to common organotin reagents can be em-
ployed.16−19 One important breakthrough was the discovery
of organoboron reagents, which exhibit low toxicity and can be
used in catalytic amounts.16−18 However, large amounts of
organobase are necessary in this method for neutralization. In
addition, only carbohydrate derivatives containing a cis-vicinal
diol motif can be selectively protected by this method. We
recently proposed a principle for organotin-mediated regiose-
lective carbohydrate protection in which the regioselectivity is
likely to be controlled by steric and stereoelectronic effects of
the parent substrate structure.7,20 Under the guidance of this
principle, an organosilicon-mediated regioselctive acetylation of
carbohydrates was developed.19 The regioselective protection
patterns are the same as those of organotin-mediated acylation
methods, while enabling similar yields. Although organosilicon
Received: June 16, 2014
© XXXX American Chemical Society
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In addition, of particular importance is the possibility of
acquiring single or multiple protections for polyols in single-
step processes. The disbutylstannylene-mediated multiple
carbohydrate esterification requires an excess (2−3 equiv) of
organotin reagent.38 We wondered if the acetylation activation
method, which supposedly proceeds via dual H bonding, could
be applied in single or multiple esterification for polyols, where
a catalytic amount of TBAOAc (0.3−0.6 equiv) would be used
instead of organotin. We here present the results of an
extensive quantum chemical study of the catalytic system
alongside further application of the methodology.
Scheme 1. Regioselective Acetylation of Diols Catalyzed by
Acetate Anion
RESULTS AND DISCUSSION
■
One classic method for the acetylation of a free glycoside
involves pyridine together with an acetylation reagent, such as
acetyl chloride (AcCl) or acetic anhydride (Ac2O). The high
rate of this reaction prohibits adequate regioselectivity, unless
very low reaction temperatures (<−40 °C) are used.39 In light
of a consensus mechanism (Figure 1a), pyridine initially forms
a highly electrophilic N-acylpyridinium counterion with the
acetylation reagent.40−42 The acylpyridinium ion then reacts
with the hydroxyl groups. It has been found that the counterion
has a strong effect on the reaction rate and that more basic
counterions lead to faster reaction rates (CN > OAc > Cl) for
DMAP-catalyzed acetylation.34,43
study, catalytic amounts of tetrabutylammonium acetate (0.3
equiv) were employed to form H-bonding complexes with
diols, leading to regioselective acetylation of the diols by acetic
anhydride. These reactions were performed under mild
conditions without the assistance of any other reagents.
Following an 1H NMR study and a tentative quantum chemical
investigation, we proposed a mechanism which involves an
initial formation of a dual H-bonded complex between the
acetate anion and the diol.37 On this basis, we speculated that
the resulting regioselectivities might also be controlled by steric
and stereoelectronic effects of the parent substrate structure,
similar to the organotin cases. Especially, the regioselectivity
might originate from the inherent structure of the diol−acetate
H-bonded complex. To the best of our knowledge, this method
is the most convenient, green, efficient, economical, and
regioselective high-yield acetylation method to date. Therefore,
the origin of the regioselectivity needs to be further elucidated.
We have also found that the acetylation of hydroxyl groups
by Ac2O is much faster than when AcCl is used in a pyridine-
catalyzed acetylation (Table 1). However, the reason for this is
still not very clear. In an earlier study, we found that
intramolecular acetyl group migration can be activated by
anions in nonpolar solvents under mild conditions.45 The
leading cause for this process has been attributed to the
formation of hydrogen bonds between neighboring hydroxyl
groups and anions. The catalytic effect of anions follows the
corresponding H-bond formation tendencies, where more basic
Figure 1. Anion-promoted acetylations by the formation of hydrogen bonding.
B
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similar to that of structure B, since their structures are very
similar (Figure 2). Thus, acetylation reactions may proceed
with the addition of anions under the same conditions as anion-
activated acetyl group migration, and furthermore, the
acetylation may show regioselectivity, since its reactivity is
much lower than that of pyridine-catalyzed acetylation. To
investigate this hypothesis, a diol model was tested in
acetylation with the addition of Ac2O and various anions.37
Our studies indeed indicated that the acetylation could be
activated by the formation of H bonds between hydroxyl group
and anions and that more basic anions lead to faster acetylation.
A range of diols were allowed to react with 1.1 equiv of Ac2O in
the presence of 0.3 equiv of TBAOAc in acetonitrile at 40 °C
for 8−24 h.37 This resulted in high regioselectivities in most
cases and excellent isolated yields, indicating that the diols can
be regioselectively acetylated when acetate is employed as a
catalyst. Though our initial mechanistic studies included a
preliminary quantum chemical study, which supported a dual
H-bond model as a viable explanation for the catalytic activity
of acetate and the origin of the regioselectivity, a more
extensive quantum chemical study was still deemed necessary.
Mechanistic Study. We chose 1,2-propanediol (3) as an
initial model system (Figure 3). To investigate possible
additional influences by sterics and dispersion forces, the
model was later expanded to a carbohydrate structure with the
identical diol structural motif (Figure 4). In order to reduce the
size of the calculation, the benzyl groups in 2- and 6-positions
in compound 6 were substituted with methyl groups, giving the
model carbohydrate (M). Geometry optimization and
frequency analysis were performed using Gaussian 0946 at the
M06-2X47/6-31+G(d,p) level of theory. Acetonitrile solvent
was treated implicitly by the SMD-PCM48 method. This was
followed by single-point energy calculations at several levels of
theory. The B2PLYP double hybrid and the M06-2X hybrid
meta exchange DFT functionals have been extensively tested in
large test sets and have reported mean absolute energy
deviations of 2.549 and 2.2 kcal/mol,50 respectively.
Table 1. Comparison of the Acetylation Rates in Pyridine-
Catalyzed Acetylations
a
reagent
(2.0 equiv)
base
(2.0 equiv)
entry
solvent
time/h conversion/%
1
2
3
4
AcCl
Ac2O
AcCl
Ac2O
Py
1
1
1
1
17
50
24
31
Py
DCM
DCM
Py
Py
a
Reaction conditions: 50 mg of reactant in 1 mL of solvent, 0 °C, 1 h.
anions lead to faster migration. A proposed mechanism is
shown in Figure 1b.
Calculations at the B3LYP/6-311+G(d,p)//6-31G(d) level
suggest that A in Figure 1a corresponds to the rate-determining
transition state structure.41 Similarly, B in Figure 1b is believed
to be the rate-determining transition state structure in acetyl
group migration. Due to the stabilizing electrophilic N-
acylpyridinium in structure A, the energy of A is lower than
that of B. This explains why the rate of pyridine-catalyzed
acetylation is higher than that of anion-activated acetyl group
migration. As for the acetylation without the catalysis of
pyridine (Figure 1d), a destabilized transition state structure D
will not allow for acetylation. In the transition structure types A
and B, stronger H bonding makes the oxygen atom of the
hydroxyl group more negatively charged, leading to further
stabilization of the transition state. Consequently, with fluoride,
acetate, chloride, and bromide anions, the energies of A and B
should follow the order A1 < A2 < A3 < A4 and B1 < B2 < B3 <
B4 (Figure 2). Arguably, this could explain the results in Table
1, in DMAP-catalyzed acetylation34,43,44 and in H-bond-
activated intramolecular acetyl group migration.45
On the basis of this analysis, an interesting question emerges:
what will happen if the N-acylpyridinium ion in the transition
state of type A is replaced by an acetylation reagent? In this
case, the reaction will go through the transition state C (Figure
1c). The barrier height corresponding to structure C should be
We found no meaningful differences (<0.4 kcal/mol) when
comparing the TZVP with the Def2-TZVPP basis sets in the
small 1,2-propanediol model (Table S1, Supporting Informa-
Figure 2. Proposed energy order of the rate-determining transition structures.
C
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Figure 3. The model reaction of 1,2-propanediol is given at the top. (A, B) Considered transition state geometries for the reaction of 1,2-propanediol
with acetic anhydride at (A) the primary position and (B) the secondary position. Reactions at the primary and secondary positions are denoted with
′ and ′′, respectively. The uncatalyzed reaction is shown as 0 (zero). The lowest transition state TS-1′ is highlighted in red. Free energies of
activation (ΔG⧧, 298 K, 1 M) are given in parentheses. All energies can be found in Table S1 (Supporting Information). (C) Schematic depiction of
the lowest transition state, where formation of a key stabilizing hydrogen bond is shown in red.
tion). However, we were surprised to obtain large (2−4 kcal/
mol) differences in transition state energies when comparing
SMD-M06-2X with COSMO-B2PLYP-D3 calculations. There-
fore, we complemented our study with the range-separated
ωB97X-D hybrid functional,51 which has demonstrated
excellent performance for proton transfer kinetics,52 as well as
for general-purpose use.53 The ωB97X-D functional was found
to consistently provide transition state energies between those
obtained with M06-2X and B2PLYP-D3. The slightly higher
barriers obtained with B2PLYP-D3 and ωB97X-D are in better
accord with our experimentally observed rates, and we are
inclined to trust these methods more in this case. The
differences in the implicit solvation models SMD and COSMO
are likely to affect values somewhat, yet large differences were
only observed when free (noncomplexed) acetate was
considered. It is important to note that the main trends
between transition state energies are preserved with all
methods, and our conclusion regarding the selectivity of
acetylation is unaffected by the choice of method or basis set.
For clarity only SMD-ωB97X-D energies are shown in the
figures (all results are provided in Table S1, Supporting
Information).
To estimate the acidity difference between the competing
OH groups, we have calculated the proton affinity of the
corresponding alkoxides in acetonitrile solution. The proton
affinity of the 2° alkoxide of 1,2-propanediol 3 is found to be
0.3 kcal/mol higher using B2PLYP-D3/Def2-TZVPP energies
Figure 4. Catalytic cycle for acetylation of the model carbohydrate M.
Green arrows show nuclear displacements in the transition state.
Relative energies (1 M, 298 K) are given in kcal/mol.
and 0.1 kcal/mol lower at the M06-2X/cc-pVTZ level. At the
ωB97X-D/cc-pVTZ level the difference in energy is only 0.01
D
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kcal/mol. These results suggest that the acidity difference is
minute and is unlikely to affect the acetylation of 1,2-
propanediol. For the carbohydrate model all three methods
agree that the axial alkoxide has a slightly lower proton affinity
(i.e., that the axial OH group is more acidic). The proton
affinity differences are 0.37, 0.22, and 0.16 kcal/mol when
calculated using B2PLYP-D3, ωB97X-D, and M06-2X,
respectively. Thus, our results indicate a slight acidity
difference, which is acting against the observed selectivity.
Figure 3 illustrates the considered transition state geometries
in the 1,2-propanediol system. The lowest transition state, and
hence the most likely rate-determining step, for reaction at the
primary alcohol group was found to be TS-1′, which
corresponds to a free energy of activation of 21.0 kcal/mol.
The lowest competing pathway, i.e. for reaction at the
secondary alcohol, was found to be TS-3″, which corresponds
to a free energy of activation of 22.1 kcal/mol. These values are
both reasonable and are in good agreement with observed rates.
The majority of all identified transition states exhibit dual
hydrogen bonding between the diol and the acetate anion. The
key difference inherent in TS-1′ lies with the specific
arrangement of the acetic anhydride in relation to the two
hydrogen bonds. This arrangement permits for motion over the
barrier while simultaneously allowing the formation of a
hydrogen bond with the newly forming acetate anion, which
is being cleaved off the reacting acetic anhydride (Figure 3C).
This hydrogen bond forms in a concerted fashion with the
progression over the barrier and acts to slightly stabilize the
system. The electronics and geometry are so that the
corresponding arrangement for reaction at the secondary
position (TS-1″, Figure 3) is higher in energy, instead causing
TS-3″ to be the lowest barrier for this competing reaction
outcome.
Figure 4 depicts the full catalytic cycle when calculated for
the model carbohydrate M. The thermodynamics and kinetics
of this cycle are very similar to those of the 1,2-propanediol
case, with near-identical barrier heights. The more stringent
steric constraints enforced by the carbohydrate backbone
prohibits several transition state geometries identified at higher
relative energies in the smaller model. For this reason, and due
to its size, a more limited number of transition state structures
were evaluated for the larger model (Figure S4, Supporting
Information).
The very slight calculated difference in energy between
competing pathways of 1.1−1.8 kcal/mol suggests a selectivity
of ∼85−95% at 40 °C in favor of acetylation at the primary/
axial position. However, as it is difficult to discern the minor
product 5 following acetylation of 1,2-propanediol, from the 1H
NMR spectra (Figure S1, Supporting Information), we cannot
provide an accurate estimate of the exact selectivity. Our
experiments with a range of substrates mostly attain an overall
yield exceeding 80% (vide infra). We can conclude that out
calculations predict a small but distinct difference in reaction
rates between competing pathways and appear to predict a
general preference for equatorial and primary hydroxyl sites.
This preference can in part be explained by the specific
structure of the diol−acetate complex, which guides the
geometry into that of a highly concerted transition state. In
this transition state one carbon−oxygen bond is broken,
another is formed, one proton is transferred from the diol to
the acetate catalyst, forming HOAc, and a stabilizing hydrogen
bond is formed that facilitates the regeneration of the acetate−
catalyst from acetic anhydride. (Figure 3C).
The lowest identified transition state with 1,2-propanediol,
TS-1′, was chosen as a model for kinetic isotope effect (KIE =
kH/kD) estimation. For our calculations both hydroxyl hydro-
gens were substituted for deuterium, while all other hydrogens
were left the same. SMD-ωB97X-D/cc-pVTZ//SMD-M06-2X/
6-31+G(d,p) calculations within the framework of transition-
state theory (TST) at 25 °C provided a KIE of 3.10. Due to the
dual hydrogen bond and proton-transfer nature of the reaction
such a large primary KIE is reasonable. Due to the quite
involved nature of the transition state, we have corrected our
TST rate estimates for quantum mechanical tunneling effects
using the approximation of Skodje and Truhlar.54 Whereas our
TST rates (@1 M and 25 °C) for the two reactions are kH =
10−3 and kD= 10−4 s−1, accounting for tunneling over the TS-1′
barrier provides corresponding rates of 3.1 e−3 and 9.8 e−4 s−1,
respectively. This translates into transmission coefficients for
the nondeuterated and deuterated cases of 1.18 and 1.15,
respectively. Our final estimate for the KIE in the acetylation of
1,2-propanediol, including tunneling, is 3.18. It should be noted
that the proper inclusion of variational effects, and the
consideration of multiple competing transition states, would
likely decrease this value somewhat. By substituting only one of
the two hydroxyl hydrogens, we can deduce that the KIE
should originate nearly completely from the atom being
transferred. Changing the isotope of the second hydroxyl
group, which in TS-1′ is rotating to form a hydrogen bond,
does not affect the value noticeably. Due to this, and the fact
that rapid exchange would render single-H/D substitution on
two bordering hydroxyl groups borderline impossible, exper-
imental KIE measurements will not be able to conclusively
prove the exact proposed nature of the transition state: i.e., the
presence of dual hydrogen bonding.
In an effort to support our computational predictions, we
1
have attempted to measure the KIE by H NMR experiments.
Our measured KIE value for 1,2-propanediol is around 2.0
under our most rigorous experimental conditions (Figures S2
and S3, Supporting Information). However, despite our best
efforts, we cannot properly evaluate the accuracy of this value
because trace amounts of water in the reaction mixture are very
hard to remove completely. Even very small amounts of water
effectively exchange its protons with the deuterons of the
sample, which has the effect of reducing the observed KIE. It is
furthermore possible that trace amounts of water can interact
with the OH/OD groups and affect the reaction mechanism in
a manner we have not considered in our theoretical models.
Nevertheless, the KIE observed for 1,2-propanediol implies that
proton transfer is occurring in the rate-determining step, in
agreement with our computational predictions.
Regioselective Acetylation of Polyols. In light of the
studies for regioselective acetylation of diols37 and the above
studies of the reaction mechanism, we propose that dual H-
bond complexes also can play key roles in the regioselective
acetylation of polyols. To investigate this, TBAOAc was tested
together with a range of free glycosides and glycerol (cf. Table
2): methyl β-D-glucoside 8, methyl α-D-glucoside 9, methyl β-D-
galactoside 10, methyl α-D-galactoside 11, methyl α-D-manno-
side 12, and methyl β-D-xyloside 13, six unprotected pyrano-
sides, and glycerol 14.
When these compounds were allowed to react with 1.1 equiv
of acetic anhydride in the presence of 0.3 equiv of TBAOAc in
acetonitrile, mixtures of 3-OAc, 6-OAc, and 3,6-di-OAc
products were obtained for the acetylation of compounds 8−
12, and good selectivities of monoacetylated products were
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Table 2. Acetate-Catalyzed Regioselective Acetylation of
Unprotected Carbohydrates
Table 3. Acetate Anion Promoted Monoacetylation of
a
a
Carbohydrate Derivatives
a
Reaction conditions: reactant (100 mg), Ac2O (2.1 equiv), TBAOAc
(0.6 equiv); (A) CH3CN, 40 °C, 8−12 h; (B) CH3CN, room
temperature, 24 h; (C) CH3CN/DMF (5/1), room temperature, 12−
18 h; (D) Ac2O (1.1 equiv), TBAOAc (0.3 equiv), CH3CN, 40 °C, 8−
b
c
d
e
12 h. Isolated yield. No reaction. Complex mixture. NMR ratio.
a
Reaction conditions: reactant (100 mg); (A) Ac2O (1.1 equiv),
TBAOAc (0.6 equiv), CH3CN, 40 °C, 8−12 h; (B) Ac2O (1.1 equiv),
TBAOAc (0.3 equiv), CH3CN, 40 °C, 8−12 h; (C) Ac2O (2.1 equiv),
obtained for the acetylation of compounds 13 and 14. When
2.1 equiv of acetic anhydride and 0.6 equiv of TBAOAc were
employed under the same conditions, 3,6-di-OAc products
(compounds 15−18) were obtained in high isolated yields. The
exception was 12, where the reaction led to complex mixtures.
Acetylation of glycerol 14 led to selective acetylation of two
primary hydroxyl groups. An important result is the acetylation
of methyl β-D-xyloside 13, in which the monoacetylation
product 19 is obtained in 93% yield. This is, to the best of our
knowledge, not possible with any other currently known
method.
The unprotected glycosides are poorly soluble in acetonitrile,
and a small amount of DMF mixed in acetonitrile can improve
the solubility and accelerate reaction rates. Reaction at room
temperature can improve regioselectivities and improve the
isolated yields.
As selectivity toward 3- and 6-positions of unprotected
glycosides was observed, we expected glycosides with either of
the 3- and 6-positions protected to show good selectivity for
the other respective position. We therefore synthesized and
further tested the following substrates (Table 3): compounds
22, 24, 26, 28, and 29, in which the 6-OH groups of
compounds 8−12 were silylated, compounds 23 and 25, in
which the 2-OH groups of compounds 8 and 9 were
benzylated, and compounds 27 and 30, in which the 3-OH
groups of compounds 10 and 12 were benzylated. As expected,
when compounds 22, 24, and 26−30 were allowed to react
with 1.1 equiv of acetic anhydride in the presence of 0.3−0.6
equiv of TBAOAc in acetonitrile, the monoacetylation 3- and 6-
OAc products 31, 33, and 35−39 were obtained in high
isolated yields (78−92%). Mixtures of the major 3-OAc and 6-
OAc products were also obtained for the monoacetylation of
compounds 23 and 25. However, it is hard to explain why the
NMR ratio 6-OAc/3-OAc was 75/25 for β-D-glucoside 23
whereas it was 29/71 for α-D-glucoside 25. When compounds
b
c
TBAOAc (0.6 equiv), CH3CN, 40 °C, 8−12 h. Isolated yield. NMR
ratio. Complex mixture.
d
23 and 25 were reacted with 2.1 equiv of acetic anhydride in
the presence of 0.6 equiv of TBAOAc in acetonitrile, complex
mixtures were obtained instead of the expected 3,6-di-OAc
products.
In most examples shown in Tables 2 and 3, the isolated
yields of the major product are quite good (>80% yield). This
directly translates into high regioselectivities (>80%). However,
because only very small amounts of side products are formed,
and due to the difficulty in isolation of these minor side
products, it is difficult to estimate the overall products
distribution exactly. For some examples with yields lower
than 80%, the product distribution, or regioselectivity, is given
1
as H NMR ratios (70/30, 75/25, and 21/79 for entry 7 in
Table 2 and entries 2 and 4 in Table 3, respectively). Thus, we
have here further demonstrated the utility of using acetate
anions to catalyze regioselective acetylation of diols and polyols.
We believe that many synthetic approaches for obtaining value-
added carbohydrate intermediates could be simplified and
expanded through the application of this method. As can be
seen (Scheme 2), the methyl β-D-taloside 40, β-D-idoside 41, β-
D-mannoside 42 and β-D-altroside 43 can be efficiently
synthesized from compounds 15 and 17 via a double-parallel
inversion55 and a triggered cascade inversion.45 These two
inversion methods were built on the development of nitrite-
mediated inversion.56−58 In addition to removing toxicity
concerns, it is evident that the regioselective acetylation method
discussed here has several decisive advantages in comparison
with the organotin method, for instance in the synthesis of
compounds 15 and 17.
In conclusion, we propose that a dual H-bonding effect plays
an important role in the acetylation of diols and polyols, in
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Scheme 2. Comparison of Acetate H-Bonding Method and the Organotin Method for the Synthesis of Value-Added
a
Carbohydrate Intermediates
a
Reaction conditions: reactant (100 mg); (a) Tf2O, pyridine, CH2Cl2, −20 to 10 °C, 2 h; (b) (i) TBANO2, toluene, 50 °C, 5−12 h, (ii) MeONa,
MeOH, room temperature, 4 h; (c) (i) TBANO2, EDA, toluene, room temperature, 4 h, then workup with acid, (ii) MeONa, MeOH, room
temperature, 4 h.
1
General Method for Obtaining H NMR Ratio of Products.
Polyol reactants (100 mg) were allowed to react with acetic anhydride
(1.1−2.2 equiv) in dry acetonitrile (1 mL) at 40 °C for 8−12 h in the
presence of tetrabutylammonium acetate (0.3−0.6 equiv). The
reaction mixtures (0.2 mL) were taken and then dried under vacuum.
which hydroxyl groups are first bound to anions through the
formation of H bonds. This effect explains why more basic
anions provide faster reaction rates in pyridine-catalyzed
acetylations. A highly regioselective acetylation of diols/polyols
has been developed, in which acetylation is enabled by catalytic
amounts of acetate. The overall mechanism and role of acetate
1
The dried mixtures were directly tested by H NMR.
Methyl 3,6-O-Acetyl-β-D-glucopyranoside (15).30 Methyl β-D-
glucopyranoside (100 mg) was allowed to react with acetic anhydride
(103 μL, 2.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the
presence of tetrabutylammonium acetate (93 mg, 0.6 equiv). The
reaction mixture was directly purified by flash column chromatography
1
has been studied by H NMR experiments, quantum chemical
calculations, and kinetic isotope effect measurements. Our
computational studies suggest that the regioselectivity can be
explained by subtle differences in the structure of the
competing transition states, where the geometries, or “sterics”,
are such that reactions at equatorial and primary hydroxyls
allow formation of a hydrogen bond, which helps facilitate the
regeneration of the acetate catalyst. The regioselectivity is thus
controlled by the inherent structure of the diol/polyol−acetate
H-bonded complex. To the best of our knowledge, this
approach to acetylation offers the most environmentally
friendly, convenient, efficient, and regioselective method to
date.
1
(hexane/EtOAc 1/5), affording 119 mg of compound 36 (83%). H
NMR (CDCl3, 400 MHz): δ 4.95 (m, 1H, H3), 4.51 (dd, 1H, J1 = 2
Hz, J2 = 10 Hz, H6a), 4.36 (dd, 1 H, J1 = 1.2 Hz, J2 = 12.4 Hz, H6b),
4.29 (d, 1H, J = 7.6 Hz, H1), 3.60 (s, 3H, OMe), 3.58−3.41 (m, 3H,
H2, H4, H5), 3.15 (s, 1H, 2-OH), 2.60 (s, 1H, 4-OH), 2.36 (s, 3H,
OAc), 2.30 (s, 3H, OAc) ppm.
Methyl 3,6-O-Acetyl-α-D-glucopyranoside (16).59 Methyl α-D-
glucopyranoside (100 mg) was allowed to react with acetic anhydride
(103 μL, 2.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the
presence of tetrabutylammonium acetate (93 mg, 0.6 equiv). The
reaction mixture was directly purified by flash column chromatography
(hexane/EtOAc 1.5), affording 112 mg of compound 38 (78%). H
NMR (CDCl3, 400 MHz): δ 5.09 (t, 1 H, J1 = 9.6 Hz, J2 = 9.6 Hz, H3),
4.82(d, 1H, J = 4 Hz, H1), 4.52−4.48 (dd, 1H, J1 = 4.8 Hz, J2 = 12.4
Hz, H6a), 4.32−4.29 (dd, 1H, J1 = 2.4 Hz, J2 = 8 Hz, H6b), 3.83−3.78
(m, 1H, H5), 3.66−3.60 (m, 1H, H2), 3.54−3.47 (m, 4H, H4, OMe),
3.01 (d, 1H, J = 5.2 Hz, 2-OH), 2.28 (d, 1H, J = 11.2 Hz, 4-OH), 2.18
(s, 3H, OAc), 2.17 (s, 3H, OAc) ppm.
EXPERIMENTAL SECTION
■
General Methods. All commercially available starting materials
and solvents were of reagent grade and were dried prior to use.
Chemical reactions were monitored with thin-layer chromatography
using precoated silica gel 60 (0.25 mm thickness) plates. High-
resolution mass spectra (HRMS) were obtained by electrospray
ionization (ESI) and Q-TOF detection. Flash column chromatography
was performed on silica gel 60 (0.040−0.063 mm). 1H and 13C spectra
were recorded with 400 and 100 MHz instruments at 298 K in CDCl3,
using the residual signals from d-chloroform (1H, δ 7.25 ppm; 13C, δ
77.2 ppm), as internal standard. Assignments were made by first-order
analysis of the spectra, supported by standard 1H−1H correlation
spectroscopy (COSY). See the Supporting Information for details on
the KIE measurements.
Methyl 3,6-O-Acetyl-β-D-galactopyranoside (17).30 Methyl β-
D-galactopyranoside (100 mg) was allowed to react with acetic
anhydride (103 μL, 2.1 equiv) in dry acetonitrile (1 mL) at 40 °C for
12 h in the presence of tetrabutylammonium acetate (93 mg, 0.6
equiv). The reaction mixture was directly purified by flash column
chromatography (hexane/EtOAc 1/5), affording 120 mg of compound
40 (84%). 1H NMR (CDCl3, 400 MHz): δ 4.86 (dd, 1H, J1 = 3.2 Hz,
J2 = 10.4 Hz, H3), 4.36−4.24 (m, 3H, H1, H6a, H6b), 4.03 (m, 1H, H4),
3.86−3.81 (m, 1H, H2), 3.74 (t, 1H, J1 = 6 Hz, J2 = 6.8 Hz, H5), 3.57
(s, 3H, OMe), 2.42 (d, 1H, J = 3.2 Hz, 2-OH), 2.34 (d, 1H, J = 5.6 Hz,
4-OH), 2.18 (s, 3H, OAc), 2.09 (s, 3H, OAc) ppm.
General Method for Regioselective Acylation of Polyols.
Polyol reactants (100 mg) were allowed to react with acetic anhydride
(1.1−2.2 equiv) in dry acetonitrile (1 mL) at 40 °C for 8−12 h in the
presence of tetrabutylammonium acetate (0.3−0.6 equiv). The
reaction mixture was directly purified by flash column chromatography
(hexanes/EtOAc 2/1 to 1/1), affording the pure selectively protected
derivatives.
Methyl 3,6-O-Acetyl-α-D-galactopyranoside (18).59 Methyl α-
D-galactopyranoside (100 mg) was allowed to react with acetic
anhydride (103 μL, 2.1 equiv) in dry acetonitrile (1 mL) at 40 °C for
12 h in the presence of tetrabutylammonium acetate (93 mg, 0.6
G
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The Journal of Organic Chemistry
Article
equiv). The reaction mixture was directly purified by flash column
chromatography (hexane/EtOAc 1/5), affording 129 mg of compound
42 (85%). 1H NMR (CDCl3, 400 MHz): δ 5.06 (dd, 1H, J1 = 3.2 Hz,
J2 = 10.4 Hz, H3), 4.85 (d, 1H, J = 4 Hz, H1), 4.35−4.20 (m, 2H, H6a,
H6b), 4.02−3.97 (m, 3H, H2, H4, H5), 3.46 (s, 3H, OMe), 2.16 (s, 3H,
OAc), 2.08 (s, 3H, OAc) ppm.
mL) at 40 °C for 12 h in the presence of tetrabutylammonium acetate
(32 mg, 0.3 equiv). The reaction mixture was directly purified by flash
column chromatography (hexane/EtOAc 1/1), affording 105 mg of
compound 36 (91%). 1H NMR (CDCl3, 400 MHz): δ 7.35−7.26 (m,
5 H, Ph), 4.75 (s, 2 H, PhCH2), 4.35−4.33 (m, 2H, H6a, H6b), 4.16 (d,
1H, J = 12 Hz, H1), 3.94 (s, 1H, H4), 3.77 (t, J1 = 8 Hz, J2 = 8.6 Hz,
H2), 3.63−3.61 (m, 1H, H5), 3.55 (s, 1H, OMe), 3.46−3.42 (dd, J1 =
3.2 Hz, J2 = 9.2 Hz, H3) 2.08 (s, 1H, OAc) ppm. 13C NMR (CDCl3,
100 MHz): δ 170.8, 137.6, 128.6, 128.2, 127.9, 103.8, 72.1, 80.2, 72.3,
72.2, 70.9, 66.3, 63.0, 56.9, 20.8 ppm. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C16H22O7Na 349.1263; found 349.1262.
Methyl 3-O-Acetyl-β-D-xylopyranoside (19).60 Methyl β-D-
xylopyranoside (100 mg) was allowed to react with acetic anhydride
(64 μL, 1.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the
presence of tetrabutylammonium acetate (55 mg, 0.3 equiv). The
reaction mixture was directly purified by flash column chromatography
1
Methyl 3-O-Acetyl-6-O-(tert-butyldimethylsilyl)-α-D-galacto-
pyranoside (37). Methyl 6-O-(tert-butyldimethylsilyl)-α-D-galacto-
pyranoside (100 mg) was allowed to react with acetic anhydride (34
μL, 1.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the
presence of tetrabutylammonium acetate (30 mg, 0.3 equiv). The
reaction mixture was directly purified by flash column chromatography
(hexane/EtOAc 1/1), affording 117 mg of compound 44 (93%). H
NMR (CDCl3, 400 MHz): δ 4.81 (t, 1H, J1 = 12 Hz, J2 = 12 Hz, H3),
4.25 (d, 1H, J = 4 Hz, H1), 4.04 (dd, 1H, J1 = 4 Hz, J2 = 4 Hz, H5a),
3.80−3.75 (m, 1H, H4), 3.54−3.45 (m, 4H, H2, OMe), 3.36−3.30 (dd,
1H, J1 = 12 Hz, J2 = 12 Hz, H5b), 2.17 (s, 3H, OAc) ppm.
1-Acetyl-O-propanetriol (20).20 Propanetriol (50 mg) was
allowed to react with acetic anhydride (57 μL, 1.1 equiv) in dry
acetonitrile (1 mL) at 40 °C for 8 h in the presence of
tetrabutylammonium acetate (98 mg, 0.6 equiv). The reaction mixture
was directly purified by flash column chromatography (hexane/EtOAc
1/1), affording 52 mg of compound 45 (71%). 1H NMR (CDCl3, 400
MHz): δ 4.22−4.12 (m, 2H), 3.97−3.92 (m, 1H), 3.73−3.58 (m, 2H),
2.11 (s, 3H) ppm.
1
(hexane/EtOAc 1/5), affording 89 mg of compound 37 (78%). H
NMR (CDCl3, 400 MHz): δ 5.02 (dd, 1H, J1 = 3.1 Hz, J2 = 10.3 Hz,
H3), 4.82 (d, 1H, J = 3.9 Hz, H1), 4.17 (d, 1H, J = 2.7 Hz, H4), 4.05 (b,
1H, H2), 3.93−3.83 (m, H6a, H6b), 3.74 (t, 1H, J = 4.5 Hz, H5), 3.41 (s,
3H, OMe), 2.15 (s, 3H, OAc), 0.87 (s, 9H, tert-butyl), 0.07 (d, 6H,
Si(Me)2) ppm. 13C NMR (CDCl3, 100 MHz): δ 171.3, 100.0, 73.6,
69.5, 69.2, 67.4, 64.0, 55.6, 26.0, 21.3, 18.4, −5.3 ppm. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C15H30O7SiNa 373.1658; found
373.1631.
Methyl 3-O-Acetyl-6-O-(tert-butyldimethylsilyl)-β-D-gluco-
pyranoside (31). Methyl 6-O-(tert-butyldimethylsilyl)-β-D-glucopyr-
anoside (100 mg) was allowed to react with acetic anhydride (34 μL,
1.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the presence
of tetrabutylammonium acetate (30 mg, 0.3 equiv). The reaction
mixture was directly purified by flash column chromatography
Methyl 3-O-Acetyl-6-O-(tert-butyldimethylsilyl)-α-D-manno-
pyranoside (38). Methyl 6-O-(tert-butyldimethylsilyl)-α-D-manno-
pyranoside (100 mg) was allowed to react with acetic anhydride (34
μL, 1.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the
presence of tetrabutylammonium acetate (30 mg, 0.3 equiv). The
reaction mixture was directly purified by flash column chromatography
1
(hexane/EtOAc 1/5), affording 91 mg of compound 31 (81%). H
NMR (CDCl3, 400 MHz): δ 4.95 (t, 1H, J = 9.5 Hz, H3), 4.25 (d, 1H,
J = 7.8 Hz, H1), 3.93 (dd, 1H, J1 = 4.9 Hz, J2 = 10.5 Hz, H6a), 3.84 (dd,
1H, J1 = 5.8 Hz, J2 = 10.5 Hz, H6b), 3.66 (t, 1H, J = 9.5 Hz, H2), 3.53
(s, 3H, OMe), 3.47−3.35 (m, 2H, H4, H5), 2.16 (s, 3H, OAc), 0.89 (s,
9H, tert-butyl), 0.08 (s, 6H, Si(Me)2) ppm; 13C NMR (CDCl3, 100
MHz): δ 172.4, 103.8, 77.8, 74.5, 72.3, 71.8, 64.7, 57.4, 26.0, 21.3, 18.4,
−5.3 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H30O7SiNa 373.1658; found 373.1628.
1
(hexane/EtOAc 1/5), affording 93 mg of compound 38 (82%). H
NMR (CDCl3, 400 MHz): δ 5.05 (dd, 1H, J1 = 3.3 Hz, J2 = 9.8 Hz,
H3), 4.66 (d, 1H, J = 1.7 Hz, H1), 4.0−3.81 (m, 4H, H2, H4, H6a, H6b),
3.66−3.59 (m, 1H, H5), 3.36 (s, 3H, OMe), 2.14 (s, 3H, OAc), 0.88
(s, 9H, tert-butyl), 0.08 (s, 6H, Si(Me)2) ppm. 13C NMR (CDCl3, 100
MHz): δ 171.4, 100.8, 74.6, 71.6, 69.2, 67.9, 64.5, 55.1, 26.0, 21.3, 18.4,
−5.3 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H30O7SiNa 373.1658; found 373.1630.
Methyl 3-O-Benzyl-6-O-acetyl-α-D-mannopyranoside (39).
Methyl 3-O-benzyl-β-D-mannopyranoside (100 mg) was allowed to
react with acetic anhydride (37 μL, 1.1 equiv) in dry acetonitrile (1
mL) at 40 °C for 12 h in the presence of tetrabutylammonium acetate
(32 mg, 0.3 equiv) The reaction mixture was directly purified by flash
column chromatography (hexane/EtOAc 1/1), affording 100 mg of
compound 39 (87%). 1H NMR (CDCl3, 400 MHz): δ 7.35−7.26 (m,
5 H, Ph), 4.78 (d, 1 H, J = 1.6 Hz, H1), 4.73−4.63 (m, 2H, PhCH2),
4.47−4.43 (dd, 1H, J1 = 4.8 Hz, J2 = 12.4 Hz, H6a), 4.32−4.29 (dd, 1H,
J1 = 2.4 Hz, J2 = 12 Hz, H6b), 4.01 (s, 1H, H4), 3.81−3.66 (m, 3H, H2,
H5, H3), 3.28 (s, 1H, OMe), 2.11 (s, 1H, OAc) ppm. 13C NMR
(CDCl3, 100 MHz): δ 171.6, 137.7, 128.7, 128.2, 127.9, 100.6, 72.1,
70.0, 67.8, 66.4, 63.5, 55.0, 20.9 ppm. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C16H22O7Na 349.1263; found 349.1263.
Methyl 3-O-Acetyl-6-O-(tert-butyldimethylsilyl)-α-D-gluco-
pyranoside (33). Methyl 6-O-(tert-butyldimethylsilyl)-α-D-glucopyr-
anoside (100 mg) was allowed to react with acetic anhydride (34 μL,
1.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the presence
of tetrabutylammonium acetate (30 mg, 0.3 equiv). The reaction
mixture was directly purified by flash column chromatography
1
(hexane/EtOAc 1/5), affording 86 mg of compound 33 (76%). H
NMR (CDCl3, 400 MHz): δ 5.06 (t, 1H, J = 9.3 Hz, H3), 4.72 (d, 1H,
J = 3.8 Hz, H1), 3.88−3.78 (m, 2H, H6a, H6b), 3.66−3.48 (m, 3H, H2,
H4, H5), 3.41 (s, 3H, OMe), 2.12 (s, 3H, OAc), 0.87 (s, 9H, tert-
butyl), 0.06 (s, 6H, Si(Me)2) ppm. 13C NMR (CDCl3, 100 MHz): δ
172.7, 99.4, 76.6, 71.2, 71.0, 70.4, 63.9, 55.4, 26.0, 21.3, 18.4, −5.3
ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H30O7SiNa
373.1658; found 373.1642.
Methyl 3-O-Acetyl-6-O-(tert-butyldimethylsilyl)-β-D-galacto-
pyranoside (35). Methyl 6-O-(tert-butyldimethylsilyl)-β-D-galacto-
pyranoside (100 mg) was allowed to react with acetic anhydride (34
μL, 1.1 equiv) in dry acetonitrile (1 mL) at 40 °C for 12 h in the
presence of tetrabutylammonium acetate (30 mg, 0.3 equiv). The
reaction mixture was directly purified by flash column chromatography
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, tables, and figures giving 1H NMR spectra of compounds
15−20, 21a,b, 31, 33, and 35−38, 13C NMR spectra of
compounds 31, 33, and 35−39, the measurement of KIE by 1H
NMR experiments, full author list of ref 46, calculated Cartesian
coordinates and energies. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
(hexane/EtOAc 1/5), affording 91 mg of compound 35 (80%). H
NMR (CDCl3, 400 MHz): δ 4.81 (dd, 1H, J1 = 3.1 Hz, J2 = 10.1 Hz,
H3), 4.23 (d, 1H, J = 7.7 Hz, H1), 4.16 (d, 1H, J = 3.1 Hz, H4), 3.96−
3.83 (m, 3H, H2, H6a, H6b), 3.55 (s, 3H, OMe), 3.50 (t, 1H, J = 5.5 Hz,
H5), 2.16 (s, 3H, OAc), 0.87 (s, 9H, tert-butyl), 0.07 (d, 6H, Si(Me)2)
ppm. 13C NMR (CDCl3, 100 MHz): δ 171.0, 104.4, 75.5, 73.8, 69.5,
68.3, 63.3, 57.2, 26.0, 21.3, 18.4, −5.3 ppm. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C15H30O7SiNa 373.1658, found 373.1634.
Methyl 3-O-Benzyl-6-O-acetyl-β-D-galactopyranoside (36).
Methyl 3-O-benzyl-β-D-galactopyranoside (100 mg) was allowed to
react with acetic anhydride (37 μL, 1.1 equiv) in dry acetonitrile (1
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail for M.R.: martinr@kth.se.
*E-mail for H.D.: hdong@mail.hust.edu.cn.
H
dx.doi.org/10.1021/jo501343x | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
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Notes
The authors declare no competing financial interest.
(32) Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem. Soc., Perkin
Trans. 1 1999, 465−473.
ACKNOWLEDGMENTS
■
(33) Kurahashi, T.; Mizutani, T.; Yoshida, J. Tetrahedron 2002, 58,
8669−8677.
This study was supported by the National Nature Science
Foundation of China (Nos. 21272083), the Chutian Project-
Sponsored by Hubei Province, and the Project-Sponsored by
the SRF for ROCS, SEM. The authors are also grateful to the
staff of the Analytical and Test Center of HUST for support
with the NMR instruments.
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