Diisopropylethylamine-triggered, highly efficient, self-catalyzed regioselective acylation of carbohydrates and diols

Article abstract of DOI:10.1039/c8ob01464g

A diisopropylethylamine (DIPEA)-triggered, self-catalyzed, regioselective acylation of carbohydrates and diols is presented. The hydroxyl groups can be acylated by the corresponding anhydride in MeCN in the presence of a catalytic amount of DIPEA. This method is comparatively green and mild as it uses less organic base compared with other selective acylation methods. Mechanistic studies indicate that DIPEA reacts with the anhydride to form a carboxylate ion, and then the carboxylate ion could catalyze the selective acylation through a dual H-bonding interaction.

Full text of DOI:10.1039/c8ob01464g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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ARTICLE
Diisopropylethylamine-Triggered, Highly Efficient, Self-Catalyzed
Regioselective Acylation of Carbohydrates and Diols
Bo Ren*a, Lu Gana, Li Zhanga, Ningning Yana and Hai Dongb
Received 00th January 20xx,
Accepted 00th January 20xx
A diisopropylethylamine (DIPEA)-triggered, self-catalyzed, regioselective acylation of carbohydrates and diols is presented.
The hydroxyl groups can be acylated by the corresponding anhydride in MeCN in the presence of a catalytic amount of
DIPEA. This method is comparatively green and mild as it uses less organic base compared with other selective acylation
methods. Mechanistic studies indicate that DIPEA reacts with the anhydride to form a carboxylate ion, and then the
carboxylate ion could catalyze the selective acylation through a dual H-bonding interaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
acylation of carbohydrates and diols. In 1988, Wong and
coworkers developed lipase-catalyzed selective acylation of
furanose and pyranose derivatives.27 Then in 2005,
Introduction
Protection strategies are long-standing challenges in
carbohydrate chemistry for the efficient preparation of high
value-added carbohydrates and site-selective synthesis of
building blocks for oligosaccharide synthesis.1-8 Regioselective
acylation is always very important in organic chemistry,9-12
especially in the synthesis of oligosaccharide building blocks
because it is convenient for the protection and deprotection of
hydroxyl groups.13-15 To date, many metal catalysts and organic
small molecules have been employed in the regioselective
acylation of diols and polyols, including tin (IV),16-18 boron
(IV),19 copper (II),20-22 and silver (I),23 as well as a recently
reported iron catalyst.24 Organotin compounds were the most
widely used reagents for the selective protection of
carbohydrate for many years as they are easy to operate and
always lead to high regioselectivity. However, organotin
reagents can be inherently toxic, so this limits their range of
Bornscheuer and coworkers developed lipase-catalyzed
glucose fatty acid ester synthesis in ionic liquids, which means
we can get high regioselectivity by enzyme catalyzed
acylation.28 In 2004, Kattnig and coworkers developed a
dimethylaminopyridine (DMAP)-catalyzed method for the
selective acetylation of octyl-β-D-glucopyranoside, which
involved low temperature reaction conditions and low
regioselectivities (Scheme 1a).31 Then, in 2007, Kawabata and
coworkers developed a DMAP-catalyzed method for the
selective acylation of octyl-6-O-methyl-β-D-glucopyranoside,
which leads to high regioselectivity for the 3-OH acylated
products, but this method required 1.5 equiv. of collidine as a
base, making it neither green nor atom economical (Scheme
1a).32 In 2013, the Tan group developed N-methylimidazole-
derived catalysts for the site-selective functionalization of
26
complex carbohydrates,15 which was
a substantial step
applications.25, The Taylor’s catalyst (diphenylboronic acid
forward for the selective recognition of hydroxyl groups.
Recently, Toda and coworkers developed a phosphonium ylide
as an ionic nucleophilic catalyst for the selective acylation of
primary hydroxyl groups of diols, and this method shows good
regioselectivity for terminal hydroxyls, but it is not widely
applicable.33
derivative, an effective nontoxic catalyst)-can catalyze
regioselective acylation of carbohydrates and diols; however, it
was not successfully applied for trans-diols.19 Recently, an
inexpensive catalyst, Fe(acac)3, was developed for the
regio/site-selective acylation of diols and carbohydrates
containing a 1,2-cis-diol;24 this is an efficient and green catalyst
that could replace toxic organotin reagents, but it also faces
challenges involving limited applicability.
Scheme 1. Comparison of this method with previously
reported methods.
In addition to metal catalyst, some enzymes27, 28 and small
organic molecules15, 29-33 are often applied in the regioselective
a) Org. Lett. 2004, 6, 945; Tetrahedron Lett. 2007, 48, 5031
OP
OP
O
O
Ac2O, DMAP (5 mol%)
Base, -78 oC - 0 o
HO
HO
HO
AcO
OP
OP
C
HO
HO
b) This work
OP
OP
O
O
Ac2O, DIPEA (20 mol%)
40 o
HO
HO
HO
HO
AcO
OP
OP
C
HO
Mild Conditions, Wide scope of substrates, Non-toxic reagents
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Here, we report an organic amine, diisopropylethylamine butyldimethylsilyloxy)-α-D-mannopyranoside,
1
,
as the
is treated
(DIPEA), which can be successfully used for the selective substrate to verify our hypothesis (Table 1). Thus,
1
acylation of over 25 examples of carbohydrates and diols in with 1.1 equiv. of acetic anhydride and 1.2 equiv. of DIPEA in
the presence of an anhydride (Scheme 1b). In these reactions, the presence of a catalyst in acetonitrile at 40 °C for 4–6 h. To
the amount of DIPEA can be reduced to only 0.2 equiv., while our surprise, when
1 is subjected to these reaction conditions,
stoichiometric or superstoichiometric organic amine is often the iron catalyst, Fe(dibm)3, affords the desired product in an
used in other acylation reactions.15, 21 It is clear that the use of isolated yield of approximately 92% (Table 1, Entry 3). Then,
a smaller amount of organic amine is more environmentally we change the catalyst to another common iron catalyst,
friendly and mild. In addition, based on our mechanism Fe(acac)3 (acac, acetylacetone), and we find a similarly good
studies, we propose that the organic amine triggered the H- isolated yield (Table 1, Entry 4). We hypothesize that the iron
bonding-activated, self-catalyzed, selective acylation of the was not involved in the reaction. Then, we change the catalyst
carbohydrates and diols.
to Cu(acac)2 and Zn(acac)2, and the same regioselectivities
(near 90%) are obtained (Table 1, Entries 5-6). From these
results, it appears that the ligand may be the key factor. Then,
0.1 equiv. of acetylacetone is used as the catalyst in the
reaction, and the isolated yield is also 92% (Table 1, Entry 7).
We immediately realize that the previously tested catalysts are
not active in this reaction.
Results and discussion
Organotin reagent-catalyzed reactions have been studied
for a long time, and it was often proposed that complex
stannylene dimer or polymer structures lead to good
regioselectivities.16 In 2012, Dong and coworkers predicted
that any reagent that could form cyclic dioxolane-type
intermediates with hydroxyl groups could achieve selectivities
similar to those seen with organotin reagents.34 Based on this,
we developed the Fe(dibm)3 (dibm, diisobutyrylmethane)
catalyst, which showed excellent regioselectivities in the
Then, we only use 1.2 equiv. of DIPEA along with 1.1 equiv.
of acetic anhydride in MeCN at room temperature, and the
same excellent yield was obtained (Table 1, Entry 8). In
contrast, when acetyl chloride is used instead of acetic
anhydride in the reaction, only 55% of the desired product is
obtained along with 40% byproduct (Table 1, Entry 9). A blank
control experiment shows that without DIPEA, no substrate
was acylated (Table 1, Entry 10). When other organic bases,
like TEA (triethylamine), pyridine and 2,4,6-collidine, are used
instead of DIPEA, all of them provide poor isolated yields of
approximately 40%-45%, and some unreacted starting material
is recovered (Table 1, Entries 11-13). When DMAP is used as
base, we only get main product in isolated yield of 65% and
some byproducts, as DMAP can form pyridinium acetate with
acetic anhydride, which often strongly accelerates acylation
reactions (Table 1, Entry 17). Then, when K2CO3 is used as the
catalyst, the desired product is obtained in an isolated yield of
82% with 10% byproduct (Table 1, Entry 14). This appears to
be an effective and green catalyst, but when it is extended to
other substrates, we often observe over acylation products
(Table 2, Entry 1), which means the alkalinity of K2CO3 is too
strong for it to be used as a selective acylation catalyst. DIPEA
is a comparatively mild organic base that has suitable steric
hindrance and alkalinity to provide good regioselectivity in the
acylation reactions. Therefore, the final optimized conditions
are 0.2 equiv. of DIPEA and 1.1 equiv. of anhydride in MeCN at
40 °C, and both the acetylation and benzoylation products
could be obtained in good isolated yields (Table 1, Entries 1-2)
(NMR tracking in supporting information Figure S18).
selective alkylation of carbohydrates and diols.35, As the
36
selective protection pattern is similar, we decide to test the
reactivity of this iron catalyst in the selective acylation of
carbohydrates and diols.
Table 1. Comparison of results using variations of the “standard
conditions”.
OTBS
OH
O
OTBS
OH
O
0.2 equiv. DIPEA,
1.1 equiv. (RCO)2O
HO
HO
HO
ROCO
1
2
OMe
MeCN, 40 o
C
OMe
Entry (RCO)2O Various Conditions
Isolated Yield %
1
Ac2O
Bz2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
AcCl
Optimized conditionsa
Optimized conditionsa
92
93
92
92
93
88
2
3
0.1 equiv. Fe(dibm)3, 1.2 equiv. DIPEA
0.1 equiv. Fe(acac)3, 1.2 equiv. DIPEA
0.1 equiv. Cu(acac)2, 1.2 equiv. DIPEA
0.1 equiv. Zn(acac)2, 1.2 equiv. DIPEA
4
5
6
7
0.1 equiv. acetylacetone, 1.2 equiv. DIPEA 92
8
1.2 equiv. DIPEA, rt.
0.2 equiv. DIPEA
Without DIPEA
91
9
55b
c
10
11
12
13
14
15
16
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
-
0.2 equiv. TEA
40b
45b
40b
82d
83
0.2 equiv. Pyridine
0.2 equiv. 2,4,6-collidine
0.2 equiv. K2CO3
0.1 equiv. DIPEA
Reaction at rt.
To test the catalytic efficiency and substrate scope of this
method, carbohydrates and diols are evaluated (Table 2). For
82
17
0.2 equiv. DMAP
65e
substrates
3 and 6, the acylated products are obtained with
a
poor selctivities (Table 2, Entries 1-5). However, by comparison
of the use of K2CO3 (Entry 1) with the use of DIPEA (Entry 2), it
can be found that no diacylated products are obtained with
the use of DIPEA, indicating the selectivity to mono-acylation.
Thus, this method may be useful for preparing two building
blocks simultaneously when these substrates are used. Next,
Reactant (50 mg), (RCO)2O (1.1 equiv.), DIPEA (0.2 equiv.), MeCN (1 mL), 40 °C,
4-6 h. b Poor or no selectivity. c Low conversion (5-10% of 2). d 10% of byproduct is
also obtained. e 30% of byproduct is also obtained.
Initially, we expect to develop an iron catalyst that could
selectively acylate diols and carbohydrates in the presence of
an anhydride and DIPEA. Initially, we choose methyl 6-O-(tert-
substrates
9
and 12 are subjected to these conditions, and
2 | J. Name., 2012, 00, 1-3
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ARTICLE
HO
OBz
HO
OH
good isolated yields (82%-89%) are obtained (Table 2, Entries
6–9). To test the substrate scope, diols 15 and 18 are used as
substrates, and high regioselectivities for the terminal hydroxyl
acylated product are observed in both reactions, and the
isolated yields are 85%-98% (Table 2, Entries 10–13). All the
tests show that this method has good catalytic activity for the
acylation of terminal hydroxyl groups.
13
B
85
18
20
Reaction conditions: A. 50 mg Substrate, 1 mL MeCN, 0.2 equiv. DIPEA, 1.1equiv.
Ac2O, 40 °C, 8-12 h. B. 50 mg Substrate, 1 mL MeCN, 0.2 equiv. DIPEA, 1.1equiv.
Bz2O, 40 °C, 8-12 h. C. 50 mg Substrate, 1 mL MeCN, 0.2 equiv. K2CO3, 1.1 equiv.
Ac2O, 40 °C, 8-12 h.
Table 3. DIPEA-Catalyzed Regioselective Acylation of Polyols.
Table 2. DIPEA-Catalyzed Regioselective Acetylation and
Benzoylation of Diols.
EntryConditions
Reactant
Product
Isolated yield (%)
OTBS
OTBS
EntryConditions
Reactant
Product
Isolated yield (%)
a/b/c (45/35/15)
OH
O
OH
O
HO
HO
HO
AcO
1
A
92
21
1
OR
O2
Ph
O
O
OH
Ph
Ph
O
OMe
OMe
O
R1O
4a,b,c
O
a:R1=H,R2=Ac
b:R1=Ac,R2=H
c:R1=Ac,R2=Ac
HO
3
OMe
1
2
3
C
A
B
OMe
OTBS
OH
OTBS
OH
O
O
HO
HO
HO
BzO
2
3
B
A
93
93
1
22
OR
O2
Ph
O
OH
O
O
O
O
OMe
OMe
R1O
4a,b
HO
3
a:R1=H,R2=Ac OMe
b:R1=Ac,R2=H
a/b (60/35)
a/b (48/45)
OMe
OTBS
O
OTBS
O
HO
HO
23
24
OMe
OR
O2
Ph
O
OMe
OH
AcO
Ph
O
O
HO
HO
O
O
HO
HO
R1O
5a,b
3
OMe
a:R1=H,R2=Bz
b:R1=Bz,R2=H
OMe
OTBS
OTBS
O
HO
HO
BzO
23
25
OMe
4
5
B
A
O
96
85
Ph
O
OMe
O
HO
Ph
Ph
O
O
HO
O
O
R1O
HO
OTBS
HO
7a,b
OMe
R2O
6
OMe
OTBS
4
A
a/b (47/46)
HO
HO
a:R1=H,R2=Ac
b:R1=Ac,R2=H
HO
HO
O
O
AcO
HO
27
26
HO
HO
OMe
OMe
Ph
O
O
O
O
HO
O
O
R1O
8a,b
OMe
R2O
5
6
B
A
a/b (45/45)
6
OMe
OTBS
O
OTBS
O
a:R1=H,R2=Bz
b:R1=Bz,R2=H
HO
HO
OH
OBn
OAc
6
7
8
B
A
B
86
99
98
BzO
HO
28
OMe
26
OMe
OBn
HO
HO
O
O
HO
BnO
HO
85
9
BnO
10
OMe
OMe
OTBS
OTBS
O
O
OH
OBn
OBz
OBn
HO
HO
HO
AcO
29
OMe
30
OMe
HO
HO
O
O
HO
HO
7
8
B
A
82
89
BnO
9
BnO
11
OMe
OMe
OTBS
OTBS
O
O
HO
HO
HO
BzO
OAc
OH
29
31
HO
HO
O
O
OMe
OMe
HO
HO
BnO
BnO
12
13
BnO
OH
BnO
OMe
OMe
OTBS
O
OTBS
O
32
OMe
33
OMe
OBz
HO
HO
HO
AcO
9
A
B
82
88
HO
HO
O
O
HO
HO
9
B
A
86
90
BnO
BnO
12
14
BnO
BnO
OMe
OMe
OTBS
O
OTBS
32
OMe
34
OMe
O
HO
HO
10
HO
OH
HO
Ph
OAc
BzO
HO
HO
HO
10
15
16
17
19
Ph
OAc
OH
HO
Ph
OH
OH
HO
Ph
OBz
OAc
OH
OH
O
O
HO
BnO
HO
BnO
11
12
A
B
85
81
11
12
B
A
98
85
35
36
15
18
OMe
OMe
HO
HO
OH
OBz
HO
HO
BnO
38
OMe
37
OMe
O
O
BnO
HO
HO
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OH
OAc
of DIPEA is added, the transformation constant of the OH
chemical shift with temperature is 3.7*10-3 K-1, and when 0.2
equiv of TBAOAc is added to the solution, the transformation
constant of the OH chemical shift with temperature is 4.8*10-3
K-1 (Figure S1 to Figure S3 in Supporting Information). These
results prove that the DIPEA did not form intermolecular H-
bonds with the substrate, and TBAOAc indeed form
intermolecular H-bonds with the substrate as predicted in the
previous work. This also means that DIPEA is only serving as a
base in the reaction for the formation of the carboxylate ion,
and it is the formation of the H-bonds between the
carboxylate ion and the substrate that activates the reaction.
Further experiments are conducted to compare the H-bond
effects with the addition of 1.0 equiv. of Ac2O, the addition of
0.2 equiv. of DIPEA and the addition of both 1.0 equiv. of Ac2O
and 0.2 equiv. of DIPEA (Figure S16 in the Supporting
Information). The results indicate that when TBAOAc formed
H-bonds with the substrates at 20 °C, the chemical shift of the
hydroxyl group moves downfield, from 3.500 to 3.810. When
DIPEA is added, the chemical shift of the hydroxyl group only
moves from 3.500 to 3.509. Finally, when DIPEA react with
Ac2O in CD3CN, 1H NMR tracking of the reaction shows the
chemical shift of the hydroxyl group moved from 3.295 to
3.507 in 20 minutes (Figure S17 in the Supporting Information).
This result also supports the proposed H-bonding-activated
mechanism, which means that when DIPEA reacts with Ac2O,
an increasing amount of carboxylate ion is formed and more
H-bonds are formed, so the chemical shift of the hydroxyl
group moves downfield as the reaction progresses.
HO
HO
O
O
13
A
D
C
89
88
85
BnO
BnO
40
OMe
39
OMe
HO
HO
OBz
OH
OH
OH
O
O
HO
HO
HO
14
15
BzO
41
OMe
42
OMe
OH
OAc
HO
HO
HO
AcO
O
O
44
OMe
43
HO
HO
OMe
OH
OBz
HO
HO
O
O
16
17
18
D
C
84
90
87
HO
BzO
45
OMe
43
HO
HO
OMe
OH
OAc
HO
HO
O
O
OMe
46
OMe
47
HO
AcO
HO
HO
OH
OBz
HO
HO
HO
BzO
O
O
D
OMe
46
OMe
48
HO
HO
Reaction conditions: A. 50 mg Substrate, 1 mL MeCN, 0.2 equiv. DIPEA, 1.1equiv.
Ac2O, 40 °C, 8-12 h. B. 50 mg Substrate, 1 mL MeCN, 0.2 equiv. DIPEA, 1.1 equiv.
Bz2O, 40 °C, 8-12 h. C. 50 mg Substrate, 1 mL MeCN, 0.1 mL DMF, 0.4 equiv.
DIPEA, 2.2 equiv. Ac2O, 40 °C, 8-12 h. D. 50 mg Substrate, 1 mL MeCN, 0.1 mL
DMF, 0.4 equiv. DIPEA, 2.2 equiv. Bz2O, 40 °C, 8-12 h.
The DIPEA catalyst is further used in the acylation of polyols
and carbohydrates with polyol structures (Table 3). For
glycosides in which the 6-OH is silylated (1, 23, 26, 29 and 32),
the 3-OH moiety is acylated in 82–99% isolated yields (Table 3,
Scheme 2. Proposed DIPEA-triggered, self-catalyzed acylation
mechanism.
Possible mechanism
Entries 1-10). For 3-OBn-protected compounds (35
the 6-OH moiety is acylated or benzoylated in isolated yields of
81%-89% (Table 3, Entries 11-13). Then, free glycosides 41 43
, 37 and 39),
R3
N
,
R3
Trigger
f
O
DIPEA + (R3CO)2O
O
and 46 are treated with 2.2 equiv. of anhydride and 0.4 equiv.
of DIPEA, and in all cases, 3,6-diacylated products are
generated with good isolated yields (84%-90%, Table 3, Entries
14-18). Good regioselectivities are observed for the acylations
of all the polyols.
HO
R2
O
R3
O
1,2
R1
HO
R2
OH
O
e
d
+
1,2
R1
RH
a
Based on the extended substrate scope experiments, this is
a very efficient and green method for the regioselective
acylation of diols and carbohydrates, but the catalytic
mechanism remains unclear. Compared with our previously
R3
O
R3
R3
R3
O
O
R3
R
or
O
O
O
O
O
R3
N
H
reported
TBAOAc-
and
TBAOBz-activated
acylation
Acyl reagent
H
O
H
O
H
R
f
reactions,37-39 it appears they all have similar selectivities and
patterns in the protection of specific substrates. Therefore, we
want to clarify the mechanism by NMR tests. By variable-
temperature NMR experiments, we can determine whether
the substrate forms H-bonds with the catalysts.40 The catalyst
(0.2 equiv of TBAOAc or 0.2 equiv of DIPEA or without catalyst)
is added to a solution of 1-phenyl-1,2-ethanediol (10 mg) in
dry CD3CN (0.5 mL), and then a series of variable-temperature
1H NMR tests are performed from 20 °C to 60 °C (Figure S4 to
Figure S15 in Supporting Information). When no catalyst is
added to the solution, the transformation constant of the OH
chemical shift with temperature is 3.4*10-3 K-1, when 0.2 equiv.
O
O
O
1,2
R1
1,2
R1
O
Self-Catalysis
R3
R2
R2
c
b
Less steric effect
Therefore, we propose a DIPEA-triggered, self-catalyzed,
regioselective acylation mechanism, as shown in Scheme 2. In
the proposed approach, the anhydride reacts with DIPEA to
form carboxylate ion
Then, carboxylate ion
e
and acylammonium intermediate
forms dual H-bonds with substrate
f
.
,
e
a
and the acyl reagent (anhydride or
less hindered hydroxyl group to generate acylated product
and regenerate carboxylate ion . It is possible that anhydride
or attacks the dual H-bonds of intermediate , and which acyl
f) selectively attacks the
d
e
f
b
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reagent is active remains unclear. Therefore, a catalytic
ARTICLE
In conclusion,
a
simple, efficient, green and widely
amount of base could effectively activate the regioselective applicable organic amine-triggered self-catalyzed method for
acylation. In addition, in the base-triggered processes, suitable the regioselective acylation of diols and carbohydrates has
steric hindrance and alkalinity of the base can lead to good been developed. Compared with other acylation methods, this
regioselectivity, which is why only DIPEA is selected as an method is more environmentally friendly because it requires
appropriate base. The catalytic process cannot be initiated less organic amine. This reaction avoids the use of
with acyl chloride (Entry 9 in Table 1) due to the lack of environmentally unfriendly metal ions, and it is operationally
carboxylate ion.
Table 4. Competitive acylation of hydroxyl groups.
simple, which may improve its applicability. In addition, based
on our mechanism studies, we proposed that the simple base
triggered the reaction, and the reaction was then activated by
the H-bonding between the generated carboxylate ion and the
diols.
Entry
1
Reactant
Product Isolated yield (%)
HO
Ph
OH
OH
HO
OAc
49
84
15
Ph
16
and
Ph
Experimental section
General: All commercially available starting materials and
solvents were of reagent grade and were used without further
purification. 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
(SDS 0.040-0.063 mm). 1H and 13C NMR spectra were recorded
with a JNM-ECZ600R/S3 instrument at 298K in CDCl3 using the
HO
OH
HO
OAc
OAc
OAc
OH
50
2
3
4
82
80
81
18
19
19
19
and
HO
OH
HO
HO
HO
HO
OH
18
51
and
and
HO
OH
OH
18
52
residual signals from CHCl3 (1H:
δ δ = 77.2
= 7.26 ppm; 13C:
HO
OH
HO
Ph
OAc
5
6
90
86
ppm) as the internal standard. 1H NMR peak assignments were
made by first-order analysis of the spectra and were supported
by standard 1H-1H correlation spectroscopy (COSY).
15
16
Ph
and 10 equiv. EtOH
OTBS
OTBS
OH
O
OH
O
21
OMe
General Method for Testing the H-bonds between the Diols
and Catalysts by Variable-Temperature NMR Experiments:
The catalyst (0.2 equiv. of TBAOAc, 0.2 equiv. of DIPEA or
without catalyst) was added to a solution of 1-phenyl-1,2-
ethanediol (10 mg) in dry CD3CN (0.5 mL), and then a series of
variable-temperature 1H NMR tests were performed from 20
°C to 50 °C.
HO
HO
HO
AcO
1
OMe
and 10 equiv. EtOH
Reaction condition: 50 mg Substrate, 1 mL MeCN, 0.2 equiv. of DIPEA, 1.0
equiv. of Ac2O, 40 °C, 8-12h.
Support for the dual H-bond-activated mechanism is also
found when diols 15 and 18 and 1.0 equiv. of their
corresponding monohydric alcohol (49 and 50) are co-reacted
with 1.0 equiv. of acetic anhydride in a competition reaction
(Table 4, Entries 1-2). Mono-acylated products 16 and 19 are
obtained from 15 and 18 in 84% and 82% isolated yields,
respectively, whereas no acylated product is obtained from 49
and 50. As proposed, only 1,2- and 1,3-diols can form stable
double H-bonded intermediates that could undergo acylation.
General Method for the Regioselective Acylation of Diols and
Polyols: Diol and polyol reactants (50 mg) were allowed to
react with anhydride (1.1-2.2 equiv.) in 1 mL of dry acetonitrile
or a mixed solvent (MeCN–DMF, 10:1) at 40 °C for 8 h to 12 h
in the presence of DIPEA (0.1–0.2 equiv.). After cooling and
evaporation of the solvent, the reaction mixture was directly
purified by flash column chromatography (hexanes–EtOAc 3:1
to 1:1) and afforded the pure selectively protected derivatives.
Spectroscopic data of all known products were in accordance
with those reported in the literature.
To test this, we compare the acylation of 1,2-propanediol (18
a 1,2-diol) with the acylations of 1.0 equiv. of 1,4-butanediol
51, a 1,4-diol) and 1,5-heptanediol (52, a 1,5-diol) using
,
(
catalytic DIPEA as the base (Table 4, Entries 3–4). Mono-
acylated product 19 (obtained from 18) is isolated in 80% and
81% isolated yields, respectively. In fact, when 10 equiv. of
Conflicts of interest
There are no conflicts to declare.
EtOH is reacted with 15 (diol) or
1 (glycoside), we also obtain
only the acylated products of the diol, and no EtOAc is found
(Table 4, Entries 5-6). All of these results support the proposed
mechanism in which the carboxylate ion activated the
regioselective acylation by dual H-bonds.
Acknowledgements
This study was supported by the Henan Key Scientific Research
Project (18A150015) and the Nanhu Scholars Program for
Young Scholars of XYNU. This study was also supported by the
Doctoral Research Foundation of Xinyang Normal University
Conclusions
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB01464G
ARTICLE
Organic & Biomolecular Chemistry
(Grant Number: 16070). The authors also thank the analysis 5370.
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