Regioselective acetylation of carbohydrates and diols catalyzed by tetramethyl-ammonium hydroxide in water

Article abstract of DOI:10.1039/c4gc00770k

A novel method for an efficient regioselective acetylation of carbohydrates and diols in aqueous solution is described. Treatment of substrates with 1-acetylimidazole, and tetramethyl-ammonium hydroxide (TMAH) in water under mild conditions gave highly regioselective acetylation for primary hydroxyl groups. This discovery provides an eco-friendly way for selective acetylation of non-protected glycosides and diols in water, avoiding the use of toxic organic solvents and the necessity of pre-protection of secondary hydroxyl groups. This journal is

Full text of DOI:10.1039/c4gc00770k

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Regioselective acetylation of carbohydrates and
diols catalyzed by tetramethyl-ammonium
hydroxide in water
Cite this: DOI: 10.1039/c4gc00770k
Received 29th April 2014,
Accepted 28th July 2014
a
a
a
a
a
a,b
DOI: 10.1039/c4gc00770k
Yuchao Lu, Peng Wei, Yuxin Pei,* Hengfu Xu, Xiaoting Xin and Zhichao Pei*
www.rsc.org/greenchem
A novel method for an efficient regioselective acetylation of carbo- hydrates and diols. It was known that carbonylimidazole
hydrates and diols in aqueous solution is described. Treatment of derivatives constitute a class of highly active acetylation
1
0
substrates with 1-acetylimidazole, and tetramethyl-ammonium reagents, particularly in preparation of esters and amides. In
hydroxide (TMAH) in water under mild conditions gave highly several cases, the carbonylimidazole derivatives have shown
regioselective acetylation for primary hydroxyl groups. This discov- superior selectivity for N-acetylation of oxindoles and indoles
1
1
ery provides an eco-friendly way for selective acetylation of non- (Scheme 1). However, the reactions mentioned above were
protected glycosides and diols in water, avoiding the use of toxic run in organic solvents because of poor water solubility of
organic solvents and the necessity of pre-protection of secondary carbonylimidazole derivatives. Inspired by this work, we
hydroxyl groups.
decided to explore the possibility of 1-acetylimidazole (AI) as
an acetylation reagent for replacing toxic and unstable acid
halides in water.
Regioselective protection of polyols and diols under mild and
eco-friendly conditions represents a central challenge in
chemical synthesis. Carbohydrates, which are important and
classic polyols, contain hydroxyl groups with similar reactiv-
ities. Regioselective protection of carbohydrates with several
hydroxyl groups is a long-standing problem. Recently, several
protection methods have been developed to this end using
certain reagents as promoters to enlarge small differences
between reactivities of hydroxyl groups in carbohydrates and
In another aspect, we sought to find an eco-friendly basic
catalyst for the acetylation of carbohydrates and diols. The
quaternary ammonium hydroxide as a classical strong organic
alkali attracted our attention due to its unique features:
1
2
+
−
4
R N OH zwitterionic form, non-toxicity, easy degradation,
good water solubility, cheap and commercial availability.
Earlier, Wang used tetraethylammonium hydroxide (TEAH) as
a catalyst for selectively protecting the primary hydroxyl group
3
diols. Examples include reactions employing organotin,
12
of ribonucleotides and ribonucleosides in DMF. Recently,
4
5
6
organoboron, organosilicon, and metal salts, an organo-cat-
tetramethylammonium hydroxide (TMAH) has been used in
7
8
alytic method, and an enzymatic method. However, many of
these promoters have short-comings in selective protection of
carbohydrates and diols, including environmental toxicity,
expensive reagents, moisture intolerance, and the necessity of
pre-protection of secondary hydroxyl groups. Hence, there is
an urgent need to find a mild, non-toxic and eco-friendly
method for selective protection of carbohydrates and diols,
where the reaction is best carried out in water since reactions
in aqueous solution have recently attracted considerable atten-
13
several important organic transformations. All these previous
studies encouraged us to investigate TMAH as a basic catalyst
in the selective acetylation of carbohydrates and diols with AI
in water.
Taking methyl α-D-glucopyranoside (1) as the substrate, the
regioselective acetylation of 1 in water was catalyzed by a base
in the presence of AI (Scheme 2). To improve the water solubi-
lity of AI, the reaction temperature was increased to 50 °C. The
catalytic effects of a range of bases, including TMAH, have
9
tion from the standpoint of green chemistry.
In this study, we sought to develop a green approach for
selective acetylation of primary hydroxyl groups in carbo-
a
State Key Laboratory of Crop Stress Biology for Arid Areas and College of Science,
Northwest A&F University, Yangling, Shaanxi 712100, People’s Republic of China.
E-mail: peizc@nwafu.edu.cn, peiyx@nwafu.edu.cn; Fax: +86 2987092769;
Tel: +86 2987091196
b
Attana AB, SE-11419 Stockholm, Sweden
Scheme 1 N-acetylation of heterocycles with carbonylazoles.
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primary hydroxyl group of various diols, good regioselectivity
and yields were also obtained. The byproduct yield is less than
8% (Fig. 1c, 1-phenyl-1,2-ethanediol acetylated byproduct 20b
only about 8%; Fig. 1d guaifenesin acetylated byproduct 30b
only about 6%).
Scheme 2 Regioselective acetylation of methyl α-D-glucopyranoside.
1
Because the H NMR spectra of the product mixture result-
ing from substrates 21 (entry 11) and 25 (entry 13) lack suitable
characteristic peaks for comparison, we isolated their bypro-
a
Table 1 Optimization of methyl α-D-glucopyranoside acetylation
ducts (22b yield 5% and 26b yield 6%) by chromatography.
c
1
Entry
Base
Yield (%) Moreover, no byproducts were detected by H NMR when the
substrates were 7 (methyl β-D-galactopyranoside, entry 4), 17,
1
2
3
4
5
6
7
8
DBU
DBN
LiOH
NaOH
30
23, and 31 (diols, entries 9, 12 and 16). To the best of our
18
35
23
26
32
45 (52 )
33
knowledge, this is the first report for regioselective acetylation
of carbohydrates and diols in water with AI as an acetylation
reagent in the presence of TMAH, where acetylation was per-
formed by transacylation reactions of imidazolides under
Na
2 3
CO
2
K CO
3
b
TMAH
TEAH
1
4
12a,15
strong basic conditions. Based on the previous studies,
we proposed a mechanism for the regioselective acetylation of
a
b
AI: 2.0 equiv., base: 0.5 equiv., temp: 50 °C, time: 24 h. AI: 3.0
c
equiv., TMAH: 1.2 equiv., Temp: 60 °C, time: 16 h. Isolated yield. primary hydroxyl groups using TMAH as a catalyst in water. In
DBU: 1,8-diazabicyclo[5.4.0]-undec-7-ene, DBN: 1,5-diazabicyclo-[4.3.0]-
non-5-ene, TMAH: tetramethylammonium hydroxide, TEAH:
this hypothesis, both primary and secondary hydroxyl groups
can be deprotonated in the presence of the strong base TMAH.
tetraethylammonium hydroxide.
The acylation of primary hydroxyl groups are more preferably
produced due to its less steric hindrance and stronger
been investigated (Table 1). As can be seen from Table 1, DBN, nucleophilicity than the other hydroxyl groups.12a,15 Moreover,
NaOH, and Na CO led to low yields (entries 2, 4 and 5). Edgar and co-workers reported that deacylation of cellulose
2
3
However, as we hoped, the best yield was obtained with TMAH triesters in DMSO by adding TBAOH aqueous solution, mainly
as the catalyst.
affording cellulose-6-O-esters, which demonstrated primary
In a series of optimization studies, methyl α-D-glucopyrano- esters are more stable than secondary esters under the basic
1
6
side was allowed to react with various quantities of TMAH (0.2 conditions.
Leino and co-workers studied the acyl
to 2.0 equiv.) in the presence of AI (1.2 to 4.0 equiv.) in water groups migration for β-D-galactopyranosides in D O, which
2
at temperature range from rt to 80 °C. It was found that methyl demonstrated secondary esters are easier to migrate to
6
-O-acetyl-α-D-glucopyranoside (2) was synthesized in the pres- produce primary esters under the basic conditions
1
7
ence of TMAH (1.2 equiv.) and 1-acetylimidazole (3.0 equiv.) at (C2⇄C3⇄C4→C6 migration).
6
0 °C in water for 16 h with an acceptable yield of 52%. It was
also observed that an amount of TMAH more than 2.0 equiv. required pre-preparation of catalysts, toxic organic solvents, or
disfavored the formation of product 2.
pre-protection of secondary hydroxide groups, the method we
Unlike the known methods, where the selective acetylation
With these findings in hand, the optimized catalyst system developed in this work has no such disadvantages, and is
found above was further used for selective monoacetylation therefore simple, eco-friendly, and highly regioselective. While
with a wide range of substrates (Table 2), including non-pro- yields are moderate, they compare quite favorably in general to
tected methyl D-pyranosides (entries 1–5), partially protected the overall yields of the complex protection, acylation, and
methyl D-pyranosides (entries 6–8) and diols (entries 9–16). deprotection sequences that can be replaced. For example,
The common feature of the substrates is that they all contain a regioselective acetylation of 7 and 3-methyl-1,3-butanediol 23
primary and one or more secondary hydroxyl groups. The reac- under the optimized conditions yielded the corresponding
tion condition has been successfully applied for the selectively acetylated products in 70% yield (see entries 4 and 12). These
monoacetylating carbohydrates and diols, where only minute results indicated that TMAH was successfully used to regio-
1
quantities of by-products were detected by H NMR (Fig. 1). selectively acylate carbohydrates as well as diols.
Especially, the non-protected methyl D-pyranosides showed
high regioselectivity for the primary hydroxy group and had
almost no secondary acetylated product (entries 1–3 and 5,
only trace amount of byproduct detected). The partially pro-
Conclusions
tected methyl D-pyranosides had good selectivity for the For the first time, an eco-friendly approach for regioselective
primary hydroxy group as well. The byproduct yield was not acetylation of carbohydrates and diols in aqueous solution has
higher than 7% (see Fig. 1a, methyl 3-O-benzyl-α-D-galacto- been developed. Highly regioselective acetylation for primary
pyranoside acetylated byproduct 12b only about 5%; Fig. 1b, hydroxyl groups can be obtained by using 1-acetylimidazole as
methyl 3-O-benzyl-β-D-galactopyranoside byproduct 14b only an acetylation reagent in the presence of TMAH, avoiding the
about 7%). When the method was expanded to protect the complex, costly, time-consuming protection and deprotection
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a
Table 2 1-Acetylimidazole used for selective acetylation of the primary hydroxyl group in carbohydrates and diols
c
Entry Substrates
1
Major products
By products
Conversion (%) Isolated yield (%) Ref.
Trace amount
60
52
18
2
3
Trace amount
Trace amount
62
64
56
59
9d
19
4
5
—
74
50
70
44
20
21
Trace amount
6
5% of 12b based on NMR
58
50
—
7
8
7% of 14b based on NMR
61
48
52
43
21
21
Trace amount
9
—
39
70
36
22
1
0
1
8% of 20b based on NMR
60
56
19
23
1
5% of 22b product was isolated 64
b
12
13
14
15
—
73
70
55
50
62
24
25
25
26
6% of 26b product was isolated 65
Trace amount
54
71
6% of 30b based on NMR
b
16
—
60
55
27
a
b
c
Reaction conditions: AI (3.0 equiv.); TMAH (1.2 equiv.). TMAH (1.5 equiv.). NMR ratio.
schemes. The acetylation reaction can be conveniently carried provide a novel approach to an environmentally benign
out in water, avoiding the use of toxic and flammable organic process for regioselective acetylation of primary hydroxyl
solvents. With these particular merits, this method will groups in carbohydrates and diols.
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2
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1
6
22 7
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