A metal-free route towards 1,5-disubstituted 1,2,3-triazolylmethylene linked disaccharides: Synthesis in a biodegradable hydroxyl-ammonium-based aqueous ionic liquid media

Article abstract of DOI:10.1016/j.tetlet.2018.07.052

Suitably protected carbohydrates were joined together using 1,5-disubstituted 1,2,3-triazolylmethylene (1,5-DTM) linkers. The DTM linker was built by the 1,3-dipolar cycloaddition reactions of a series of sugar azides with vinyl sulfonylmethylene-modified furanose or pyranose under metal free conditions. Three different biodegradable hydroxylammonium based ionic liquids were studied in water as the reaction media. The N,N-dimethyl ethanolammonium formate-water mixture was found to be the best reaction medium because the reaction time was shortened considerably to generate a dozen new 1,5-DTM-linked disaccharides.

Full text of DOI:10.1016/j.tetlet.2018.07.052

Accepted Manuscript
A metal-free route towards 1,5-disubstituted 1,2,3-triazolylmethylene linked
disaccharides: synthesis in a biodegradable hydroxyl-ammonium-based aque-
ous ionic liquid media
Anirban Kayet, Tanmaya Pathak
PII:
S0040-4039(18)30933-X
https://doi.org/10.1016/j.tetlet.2018.07.052
TETL 50161
DOI:
Reference:
Tetrahedron Letters
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14 June 2018
20 July 2018
23 July 2018
Please cite this article as: Kayet, A., Pathak, T., A metal-free route towards 1,5-disubstituted 1,2,3-
triazolylmethylene linked disaccharides: synthesis in a biodegradable hydroxyl-ammonium-based aqueous ionic
liquid media, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.052
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A metal-free route towards 1,5-disubstituted
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synthesis in
a
biodegradable hydroxyl-
ammonium-based aqueous ionic liquid media
Anirban Kayet, Tanmaya Pathak*

1
Tetrahedron Letters
A metal-free route towards 1,5-disubstituted 1,2,3-triazolylmethylene linked
disaccharides: synthesis in a biodegradable hydroxyl-ammonium-based aqueous ionic
liquid media
Anirban Kayet and Tanmaya Pathak
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Suitably protected carbohydrates were joined together using 1,5-disubstituted 1,2,3-
triazolylmethylene (1,5-DTM) linkers. The DTM linker was built by the 1,3-dipolar
cycloaddition reactions of a series of sugar azides with vinyl sulfonylmethylene–modified
furanose or pyranose under metal free conditions. Three different biodegradable
hydroxylammonium based ionic liquids were studied in water as the reaction media. The N,N-
dimethyl ethanolammonium formate-water mixture was found to be the best reaction medium
because the reaction time was shortened considerably to generate a dozen new 1,5-DTM-linked
disaccharides.
Available online
Keywords:
vinyl sulfone
ionic-liquid
2009 Elsevier Ltd. All rights reserved.
1,5-disubstituted 1,2,3-triazole
triazolylmethylene linked disaccharides
1,3-dipolar cycloaddition
we have established that vinyl sulfones effectively act as an
acetylene equivalent and upon reaction with organic azides
regioselectively produced 1,5-DTs.10 We extended this strategy
to prepare 1,5-DT modified carbohydrates as well as 1,5-DT
linked disaccharides and trisaccharides.3a,11 A selected group of
1,5-DT linked disaccharides were shown to generate biologically
active silver nanoparticles11b or to be effective inhibitors of
ribonuclease A.11d
Notably, a 1,5-disubstituted 1,2,3-triazolylmethylene (1,5-
DTM) linked disaccharide was also identified for the first time as
a potential inhibitor of ribonuclease A.11d The extra methylene
bridge connecting the 1,5-DT ring and the sugar residue could
increase the flexibility of 1,5-DTM linked molecules and lead to
new classes of biologically interesting molecules. We therefore
elected to further develop the synthetic strategy for the
preparation of 1,5-DTM linked carbohydrates.
The 1,2,3-triazole moiety is an important heterocyclic
scaffold known for its widespread applications.1 Since the
discovery of the Cu(I) mediated regioselective method (CuAAC)
for the synthesis of 1,4-disubstituted 1,2,3-triazoles (1,4-DTs),2
the use of the 1,2,3-triazole motif has proliferated. However, in
comparison, strategies for the synthesis of 1,5-disubstituted
1,2,3-triazoles (1,5-DTs) have achieved limited success.3,4
Although the ruthenium(II) catalyzed azide-alkyne cycloaddition
(RuAAC) is the most popular method4 to afford 1,5-DTs, the
reaction conditions are less efficient compared to the Cu(I)
mediated methods.2 In addition to ruthenium salts, the use of
cerium, zinc, samarium, palladium or nickel salts in 1,5-DT
synthesis,3,4 has raised significant concern about the presence of
residual toxic metals in the final compounds. Due to the broad
applications of 1,4-DTs and the potential usefulness of 1,5-DTs,
significant effort has been made to develop milder, simpler, and
metal-free routes to access the latter group of heterocycles.1d,5,6
Carbohydrates are frequently used as a major source of
One of our major focuses was to reduce the reaction time
required for triazole formation. Previous attempts to reduce the
reaction time by varying the conventional solvents failed.
However, it has been established that using ionic liquids (ILs) as
the reaction media influences the rates of 1,3-dipolar
chiral starting materials in organic synthesis7 and are considered
to be a major source of drug molecules.8 Although 1,4-DT
functionalized carbohydrate derivatives have been synthesized in
reasonably large numbers using Cu(I) catalysts,8f,9 there are only
a limited number of reports on the synthesis of 1,5-DT
cycloaddition reactions.12 The reactions of asymmetrically
substituted acetylenes and morpholino nitroethylene with organic
azides in ILs were 3-5 times faster and more regioselective than
the same reactions in conventional organic solvents.12b In some
cases ILs may even help switch the mechanism from concerted to
step-wise12c and thereby influence the reaction rate. Our initial
work in this area established that readily accessible and
inexpensive ILs, such as N,N-dimethyl ethanolammonium
functionalized carbohydrates in the post-click era.3a To this end,
*Corresponding author.
Tel. : +91(3222)283342 ; fax : +91 (3222)282252 ;
e.mail : tpathak@chem.iitkgp.ac.in
———

2
Tetrahedron
formate (DAF), N,N-dimethyl ethanolammonium acetate
was used for the synthesis of further 1,5-DTM-linked
disaccharides.
(DAA) and N,N-dimethyl ethanolammonium chloride (DAC),
were useful in considerably reducing the reaction time.11c
Additionally, it has been established that
hydroxyethylammonium based ILs show promising
biodegradability and toxicity results and therefore possess an
improved green profile in comparison to other ILs.13 We
therefore, decided to study the synthesis of 1,5-DTM linked
disaccharides in the “green” IL-water solvent system.
Two model compounds, a vinyl sulfone-modified
pentofuranoside 1 and a vinyl sulfone-modified hexopyranoside
2, were selected as the starting compounds (Fig. 1).
Figure 2. Azido sugars used in the 1,3-dipolar cycloaddition reaction
Figure 1. Vinyl sulfones used in the 1,5-triazolylation reactions
Thus, allyl protected carbohydrate 314 was treated with 75%
aqueous acetic acid at 75 oC to afford diol 4. Compound 4 was
benzylated with benzyl bromide in the presence of NaH in DMF
at 0 oC to afford dibenzylated compound 5 which upon treatment
with sodium para-toluene sulfinate in the presence of potassium
iodide, sodium periodate and catalytic glacial acetic acid in
acetonitrile at 40-45 oC afforded the desired vinyl sulfone-
modified pentofuranoside 1 (Scheme 1).15
Scheme 3. Synthesis of 1,5-DTM linked disaccharide 14
Table 1. Synthesis of 1,5-DTM linked disaccharide 14 in an aqueous ionic-
liquid (1:1 water/IL) media.
Vinyl
sulfone
(1 equiv.)
Azide
(1.5
equiv.)
Ionic
Liquid
Time
(h)
Yield
(%)
Product
Solvent
water
water
water
water
-
48
24
30
30
70
76
72
70
1
1
1
1
9
9
9
9
14
14
14
14
DAF
DAA
DAC
Scheme 1. Synthesis of vinyl sulfone 1
Following the same strategy,15 vinyl sulfone modified
hexopyranoside 2 was synthesized from allyl protected
carbohydrate 7 which was obtained from carbohydrate 616 by
treatment with allyl bromide in the presence of NaH in DMF at
room temperature (Scheme 2).
The 1,3-dipolar cycloaddition reactions between vinyl
sulfone modified pentofuranoside 1 and azidosugars 8, 10-13 in
aqueous DAF (1:1 v/v) at reflux afforded 1,5-DTs 15-19 in good
to high yields (Scheme 4). In order to unambiguously establish
the structures of compounds 14-19, the corresponding
regioisomeric 1,4-DTM-linked disaccharides were synthesized
using the Cu(I) strategy.2 Thus, compound 2017 was treated with
75% aqueous acetic acid to afford the free diol 21 which upon
benzylation afforded sugar alkyne 22 (Scheme 5). This sugar
alkyne was then subjected to the 1,3-dipolar cycloaddition
reaction with azido sugars 9 and 12 under CuAAC conditions2 to
afford 1,4-DTM linked disaccharides 23 and 24 in excellent
yields (Scheme 5). A comparison of the 1H- and 13C-NMR
spectra for the 15/23 and 17/24 pairs established the difference in
the triazole ring structures.
Scheme 2. Synthesis of vinyl sulfone 2
Precursors 1 and 2, were then subjected to 1,3-dipolar
cycloaddition reactions with azido sugars 8-133a,11a (Fig. 2).
Initially, vinyl sulfone 1 was reacted with 9 in water at reflux to
give 1,5-DTM linked disaccharide 14 in 70% yield after 48 h
(Scheme 3), which was significantly longer compared to our
previous reports on the synthesis of 1,5-DT-linked
Analysis of the 13C-NMR data using reported strategies18
was also used to establish the structures of isomers 14-19. Thus,
the differences in the chemical shift values of C4 and quaternary
C5 of 1,5-DTMs 14-19 ranged between 133.3-133.9 ppm and
133.3-134.9 ppm, making Δ (δC4–δC5) values significantly smaller
(ca. -1.5 ppm to +0.6 ppm). The chemical shift values of
quaternary C4 and C5 of 1,4-DTs 23 and 24 ranged between
144.7-144.9 ppm and 123.4-123.8 ppm, respectively, and
provides larger Δ (δC4–δC5) values (ca. 20.9-21.5 ppm). These
comparisons are in line with the proposed strategy18 for structural
analysis to differentiate between 1,4-DTs and 1,5-DTs.
carbohydrates.3a,11a,b,d We then studied the formation of 1,5-DT
14 (Scheme 3) using a mixture of DAA, DAC or DAF and water
(1:1 water/IL). The results are summarized in Table 1. Among
the ILs used, DAF was the most efficient in terms of cleaner
product formation as well as shorter reaction time, and therefore

3
Scheme 4. Synthesis of 1,5-DTM-linked disaccharides 15-19 from vinyl
sulfone-modified carbohydrate 1
Scheme 6 Synthesis of 1,5-DTM-linked disaccharides 25-30 from vinyl
sulfone-modified carbohydrate 2
In conclusion, we have demonstrated that easily
accessible vinyl sulfonylmethylene-modified furanosides and
pyranosides can be used to generate novel 1,5-DTM-linked
disaccharides. The use of a mixture of a biodegradable ionic-
liquid and water considerably shortened the reaction time and
improved the quality of the 1,5-DTMs in comparison with
conventional solvents. The synthesis of a small library of new
disaccharides also established the efficiency of our strategy.
Acknowledgments
T. Pathak thanks the Department of Science and
Technology (DST), New Delhi for financial support (SB/S1/OC-
30/2014). A. Kayet thanks the Council of Scientific and
Industrial Research for a fellowship. D.S.T. is also thanked for
creation of the 400 MHz facility under the I.R.P.H.A. program.
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5
Highlights
 Vinyl sulfones undergo 1,3-dipolar
cycloaddition reaction as acetylene
equivalent
 Vinyl sulfonylmethylene-modified sugars
are prepared from propargylated sugars
 These 2 partners and azidosugars react
under metal-free conditions
 A biodegradable ionic-liquid and water
mixture considerably shortenes reaction
time
 1,5-Disubstituted 1,2,3-triazolylmethylene
linked disaccharides are synthesized