Synthesis of 2,3-unsaturated alkynyl O-glucosides from tri-O-acetyl-d-glucal by using montmorillonite K-10/iron(III) chloride hexahydrate with subsequent copper(I)-catalyzed 1,3-dipolar cycloaddition

Article abstract of DOI:10.1055/s-0034-1378829

Two strategies were considered for the synthesis of 2,3-unsaturated O-glucosyl-1,2,3-triazoles. The first, involving reaction between tri-O-acetyl-d-glucal and triazole alcohols gave no stereoselectivity. A second strategy provided 2,3-unsaturated O-glyco

Full text of DOI:10.1055/s-0034-1378829

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3529–3541
paper
3529
V. N. Melo et al.
Paper
Synthesis
Synthesis of 2,3-Unsaturated Alkynyl O-Glucosides from Tri-O-
acetyl-D-glucal by Using Montmorillonite K-10/Iron(III) Chloride
Hexahydrate with Subsequent Copper(I)-Catalyzed 1,3-Dipolar
Cycloaddition
Valentina Nascimento Melo
Willyenne Marília Dantas
Celso Amorim Camara
N–
O
OAc
N+
N
O
O
X
+
AcO
Ronaldo Nascimento de Oliveira*
O
O
O
O
OAc
HO
Laboratório de Síntese de Compostos Bioativos, Universidade
Federal Rural de Pernambuco, 52171-900, Recife, PE, Brazil
ronaldonoliveira@dcm.ufrpe.br
X
N
N
O
X
OAc
AcO
N
OH
+
N
ronaldon38@gmail.com
O
N
O
X
N
10 examples
62–86% yield
AcO
OAc
O
Received: 29.04.2015
Accepted after revision: 25.06.2015
Published online: 13.08.2015
ous Lewis acids used. Gómez and co-workers8 have re-
viewed a wide range of conditions for the reaction and they
have presented comparative studies of various acceptor and
donor substrates, catalysts, solvents, temperatures, reaction
times, yields, selectivities, and workups. Among the condi-
tions and Lewis acids used for O-glycoside syntheses
through allylic rearrangement are catalysis by palladium,1
iodine monobromide,9 copper(II) triflate,10 zinc(II) bro-
mide,11 titanium trichloride monotriflate,12 bromodimeth-
ylsulfonium bromide,13 tellurium(IV) chloride,14 gold(III)
chloride,15 indium(III) chloride,16 or niobium(V) chloride,17
as well as microwave irradiation,18,19 the use of ionic liq-
uids,20 or the use of montmorillonite K-1021 or montmoril-
lonite K-10-supported bismuth(III) triflate.22
DOI: 10.1055/s-0034-1378829; Art ID: ss-2015-m0272-op
Abstract Two strategies were considered for the synthesis of 2,3-un-
saturated O-glucosyl-1,2,3-triazoles. The first, involving reaction be-
tween tri-O-acetyl-D-glucal and triazole alcohols gave no stereoselectiv-
ity. A second strategy provided 2,3-unsaturated O-glycosides from
glycals and alkynols through a Ferrier rearrangement; this method, em-
ploying montmorillonite K-10 doped with iron(III) chloride hexahydrate
in dichloromethane afforded new glycosides in good to excellent yields
within short times and with high α-stereoselectivities. Subsequently,
the glucosides were coupled with 2-azido-1,4-naphthoquinone to pro-
duce a new series of 1,2,3-1H-triazolyl O-glucoside derivatives through
a click reaction.
Key words rearrangements, triazoles, glycosides, alkynes, copper,
Iron is one of the most abundant metals on earth; con-
sequently, it is inexpensive, ecofriendly, and has been wide-
ly investigated in organic synthesis.23 In the last decade,
iron salts have been used as Lewis acids in Ferrier reactions.
Examples include iron(III) chloride,24 iron(III) chloride com-
bined with an ionic liquid,25 iron(III) nitrate,26 iron(III) sul-
fate under microwave irradiation,27 iron(III) triflate,28 and
iron(III) chloride hexahydrate/chloroform.29 While we were
preparing this manuscript, Zhou and co-workers described
the use of iron(III) chloride hexahydrate as a catalyst.30
Copper(I)-catalyzed azide–alkyne cycloaddition31 has
been employed to give 1,4-disubstituted 1,2,3-triazoles
through the concept of click chemistry. Some examples of
this reaction are based on carbohydrate frameworks.2b,32
The synthesis of 1,2,3-triazolyl glycoside derivatives from
glycals has been recently reported;33–35 molecular iodine33
and boron trifluoride etherate34 have been used as Lewis
acids in the glycosylation steps. Yadav and co-workers35 de-
click reactions
Carbohydrate chemistry has grown rapidly as a result of
its importance in glycoscience, biochemistry, and biology. A
diversity of strategies have been described for the synthesis
of building blocks of neoglycoconjugates.1,2 With regard to
new approaches for synthesizing natural scaffolds, glycals
have been used as versatile chiral synthetic intermediates
in total syntheses such as those of (+)-apicularen A,3 (+)-
blasticidin S,4 and cryptopyranmoscatone A1.5
The glycosylation reaction is a protocol that permits the
linking of a donor (a sugar moiety) with an anomeric acti-
vated leaving group and a nucleophilic acceptor (e.g., an al-
cohol or glycosyl compound).6 The Type I Ferrier reaction is
a well-known protocol for the preparation of 2,3-unsaturat-
ed O-glycosides from glycals.7,8 To promote this reaction,
various procedures have been used. The main modifica-
tions in these methodologies have been related to the vari-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3529–3541

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V. N. Melo et al.
Paper
Synthesis
such as antitumor,36a anti-Trypanosoma cruzi,36b antifungal,
strategy 1
N
and antiviral activities.36c Lin and co-workers described one
O
O
OH
O
O
N
N
X
N3
example of
a
β-C-glucopyranosyl-1,4-naphthoquinone
alkynol 2
linked to a triazole nucleus that showed activity as an in-
hibitor of phosphotyrosine phosphatase 1B.36d As part of
our interest in the synthesis of 1,2,3-triazolyl glucosides
conjugated with 1,4-naphthoquinone, we reported some
time ago a single example of a 1H-1,2,3-triazol-4-yl gluco-
side;37 on that occasion, we used montmorillonite K-10 as a
catalyst to promote the allylic rearrangement, but no de-
tailed study was performed.
In attempts to prepare 1H-1,2,3-triazol-4-yl glucosides,
we investigated two strategies (Scheme 1) with respect to
the effects of the workup and reaction time on the yield and
stereoselectivity.
3
1
4
O
OAc
O
N
X
AcO
N
O
O
N
10
First, we examined strategy 1 for the synthesis of 1H-
1,2,3-triazol-4-yl glucosides (Scheme 1). The 1,3-dipolar
cycloaddition conditions that we previously developed37
were used to promote the reaction of 2-azido-1,4-naphtho-
quinone 1 with the alkynols 2b–d (Scheme 2). The corre-
sponding products 3b–d were obtained in 81–94% yield.
Next, we used Toshima’s protocol (montmorillonite K-
10 in refluxing dichloromethane)21 for the synthesis of O-
glucosides 10b–d with yields of 59, 51, and 54%, respective-
ly. However, these reactions provided no stereoselectivity
(α/β = 1:1). The α/β ratio was determined from the 1H NMR
spectra. The signals of the anomeric hydrogen appeared as
a broad singlet at various chemical shifts (δαH-1 ≈ 5.05 ppm
and δβH-1 ≈ 5.15 ppm), with identical integrations (1 H) for
each signal.
1
OAc
AcO
OAc
O
O
O
alkynol 2
X
AcO
OAc
5
4
strategy 2
Scheme 1 Two strategies for the synthesis of 1,2,3-1H-triazol-4-yl glu-
cosides
scribed a tandem Ferrier/click reaction that uses a cop-
per(II)triflate/trimethylsilyl azide/copper system to obtain
triazole glycoconjugates.
1,4-Naphthoquinone has a well-established chemistry
and it has been identified with many biological activities,
O
OH
X
N
OAc
O
O
N3
ii
i
N
N
O
N
X
AcO
OAc
O
N
O
N
X
O
HO
O
O
10b
(59%, α/β = 1:1)
(51%, α/β = 1:1)
(54%, α/β = 1:1)
3b–d
AcO
2b X = (CH2)2
2c X = (CH2)3
2d X = (CH2)4
1
10c
10d
OAc
4
(81–94%)
O
O
OAc
N
O
O
HO
N
X
N+
AcO
MK10
O+
β-attack
Scheme 2 Synthesis of 2-(1H-1,2,3-triazol-4-yl)-1,4-naphthoquinones by strategy 1. Reagents and conditions: (i) CuI, MeCN, 12 h; (ii) MK10, CH2Cl2,
reflux, 3 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3529–3541

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V. N. Melo et al.
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Synthesis
In O-glycosylation reactions of glycals, the α-isomer is
usually predominant, due to an anomeric effect.38 The for-
mation of the β-anomer in the same ratio as the α-anomer
can be explained by an intramolecular SN2′ mechanism. The
use of an intramolecular SN2′ reaction to explain stereose-
lectivity in glycosylation reactions has been reported in the
literature.17,39 We believe that montmorillonite K-10
(MK10) can coordinate with the nitrogen sites of the tri-
azole ring, because of their basicity. The carbonyl group at
the C-3 position can also interact to favor β-attack.40,41
We then turned our attention to strategy 2, beginning
with the preparation of the O-glucosyl alkynes by using
montmorillonite K-10 (30 wt% with respect to triacetate
4).21 This gave O-glucosyl alkyne 5a in 81% yield after three
hours (Table 1, entry 1). Similar conditions gave compound
5c in a moderate yield of 44% (entry 3), but failed to give 5e
from 2-methylbut-3-yn-2-ol (2e) (entry 7). Actually, only
few methods have been successfully used with tertiary al-
cohols in the Ferrier reaction.12,14,42–43 To optimize the reac-
tion with tertiary alcohols, we decided to dope the mont-
morillonite K-10 (MK10) with 5 mass% of iron(III) chloride
hexahydrate. Experiments with 10% (w/w of 4) of the
iron(III)-doped clay produced satisfactory results only for
primary alcohols (not shown). On the other hand, with 20%
(w/w of 4) of the iron(III)-doped clay, we obtained com-
pound 5e with a yield of 80% after 10 minutes (entry 8). Un-
der these optimized conditions, glucosides 5a and 5c were
obtained in 93% and 81% yield, respectively (entries 2 and
4). This procedure was not suitable for reactions with the
more-hindered nucleophile 1,1-diphenylprop-2-yn-1-ol.
We also attempted to use iron(III) chloride hexahydrate
as the sole catalyst; however, even after three hours at the
reflux, the reaction remained incomplete (entry 5). Tan and
co-workers obtained similar results, but their reaction was
completed when the solvent dichloromethane was replaced
with chloroform, and anhydrous iron(III) chloride was used
as the catalyst.29 With our catalyst [MK10-(5% FeCl3∙6H2O)]
at room temperature, the products 5c and 5e were obtained
in yields of 55 and 48%, respectively; moreover, substrate 4
was also recovered (entries 6 and 9).
As shown in Table 1, a synergistic effect of MK10 and
iron(III) chloride hexahydrate was observed in the Ferrier
reaction in refluxing dichloromethane, as the number of
Lewis acid sites increased when only 1 mol% of iron(III)
chloride was used.
The 2,3-unsaturated alkynyl O-glucosides 5a–j were
synthesized under our established optimal reaction condi-
tions [20% MK10-FeCl3∙6H2O, CH2Cl2, reflux, 10 min (see Ta-
ble 1, entries 2, 4, and 8)]. Glucosides 5a–j were obtained in
good to excellent yields of 80–98% (Table 2).
As expected,7–30 the conformation of compounds 5a–j
was established as OH5 from the large 3J4,5 coupling constant
(8.6–10.1 Hz). The shift of the anomeric protons (δαH-1) for
compounds 5a–d ranged from 5.02 to 5.24 ppm; for 5e–h
and 5j, it ranged from 5.37 to 5.73 ppm, due to an anisotro-
pic effect on H-1 resulting from its proximity to the alkyne
Table 1 Optimization of Conditions for the Ferrier Reactiona
Entry
Catalyst
Yieldb (%)
Time
Product
AcO
O
1
2
MK10
81
93
3 h
AcO
O
MK10/FeCl3·6H2O
10 min
5a
3
4
5
6
MK10
44
81
3 h
10 min
3 h
OAc
O
O
MK10/FeCl3·6H2O
FeCl3∙6H2O
c
–
AcO
MK10/FeCl3·6H2Od
55
3 h
5c
OAc
O
7
8
9
MK10
trace
80
3 h
AcO
O
MK10/FeCl3∙6H2O
MK10/FeCl3∙6H2Od
10 min
3 h
48
5e
a Reaction conditions: CH2Cl2, reflux.
b Yield after chromatographic separation.
c Incomplete reaction.
d At r.t. (30 °C). The starting material was recovered.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3529–3541

3532
V. N. Melo et al.
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Synthesis
group (Figure 1). Furthermore, the anomeric configurations
of 5a and 5e were determined by NOESY experiments,
which confirmed that H1 and H4 were on the same side. The
1H NMR spectra of the compounds 5a–j showed that the α-
anomer was the major product, with α/β ratios of 3:1 to
10:1.
We propose the following mechanistic pathway. First,
complexation of the Lewis acid (xMn+) with the C3 acetyl
group results in complex A, with a synergistic effect when
the MK10 is doped with iron(III) chloride (Scheme 3). Sub-
sequently, elimination of the acetyl group produces an al-
R1
R2
δ(H-1) (ppm)
NOESY
O
H
H
5.24
5.37
5a
5f
H4
H1
O
H
Me
Me
Et
AcO
AcO
R2
Me
Et
5.65
5.65
5.73
5e
5j
R1
H5
OH5
–(CH2)5–
5g
Figure 1 Anisotropic effects on δH-1 in the O-glucosides
lylic oxocarbenium ion (intermediate B), the conversion of
which into intermediate C is helped by the neighboring ace-
Table 2 Synthesis of 2,3-Unsaturated Alkynyl O-Glucosides
Major product
Yielda (%) (α/β ratio)b
Ref.
Major product
Yield (%) (α/β ratio)b
Ref.
15
OAc
AcO
O
O
93 (5:1)
15,29
95 (–)c
AcO
O
AcO
O
5a
5f
OAc
OAc
O
O
O
AcO
92 (3:1)
14
86 (5:1)
O
AcO
5b
5g
OAc
OAc
O
O
O
AcO
O
81 (5:1)
44
90 (–)c
AcO
5c
5h
OAc
OAc
O
O
O
AcO
O
98 (10:1)
97 (–)c
AcO
5d
5i
OAc
OAc
O
O
AcO
O
80 (6:1)
14
AcO
O
90 (3:1)
5j
5e
a Isolated yield.
b Determined by 1H NMR.
c Not determined (complex diastereoisomeric mixture).
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3533
V. N. Melo et al.
Paper
Synthesis
tyl group on C-4. Anchimeric assistance by a bulky protect-
ing groups at the C-5 position to explain the formation of
an α-anomer has already been described in the litera-
ture.7,45 The transition-states D/D′ have their β-face sterical-
ly blocked by anchimeric assistance from the acetoxymeth-
yl group. Finally, nucleophilic α-attack on D/D′ leads to the
protonated species E and, subsequently, the major products
5a–j.
In addition, when 5a (α/β = 5:1) was treated with 20%
MK10-(5% FeCl3∙6H2O) in refluxing dichloromethane for 30
minutes, the anomeric ratio remained unchanged, i.e. no
anomerization occurred.
is known that 1,2,3-triazoles are potentially versatile li-
gands for metal coordination.47 It is therefore likely that the
strong basicity of the 1,2,3-triazole alcohol quenched the
acidity of the FeCl3-doped MK10 clay (Figure 2). This could
be indicative of a Lewis-acid property over the catalyst, but
is inconclusive regarding any redox effect.
X
N
O
O
FeCl3/MK10
N
N
Attempts to recycle the catalyst were moderately effec-
tive. Unlike an aza-Michael reaction, where preheating of
the MK10-FeCl3 at 120 °C was required,46 we used a catalyst
that was not pretreated at high temperature, making the
catalyst more ecofriendly; moreover, the low catalyst load-
ing makes the current protocol economical.
Continuing on, we applied our new procedure as strate-
gy 1, with the aim of finding an effective approach to the
reaction of 1,2,3-triazole alcohols and tri-O-acetyl-D-glucal.
Surprisingly, no reaction occurred, even after three hours. It
O
Figure 2 Hypothesis for quenching of 1,2,3-triazole alcohols in Lewis
acid catalysis
To evaluate the efficiency and generality of the catalyst
system, we used two other glycals: 3,4,6-tri-O-benzyl-D-
glucal (6) and 3,4,6-tri-O-acetyl-D-galactal (8) (Scheme 4).
When glucal 6 was treated under the conditions shown in
Table 2, the reaction with propargyl alcohol (2a) afforded
glycoside 7a in 72% yield with an α/β ratio of 2:1 (Scheme
[MK10-(5% FeCl3⋅6H2O)]
OAc
OAc
O
O
O
xMn+
X
4
AcO
AcO
OAc
5a–j
major products
O
O
O
O
+
O
+ AcOH
OAc
OAc
O
C
O
A
AcO
O
AcO
O
O+
O+
O
O+
xMn+
O–
AcO
O
X
E
H
α-stereoselectivity
B
‡
O
O–
O
O
δ+
AcO
O
OH
X
CH
2a–j
TS-D
O
O
δ+
AcO
O
CH
TS-D'
Montmorillonite: Al3.33-Mg0.67)Si8O20(OH)4.M+10.67 (nH2O)
xMn+ = Fe3+, Al3+, Ca2+, Na+, Li+, K+
α-attack
Scheme 3 Proposed mechanistic pathway to alkynyl O-glucosides with MK10/FeCl3·6H2O
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3529–3541

3534
V. N. Melo et al.
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Synthesis
4). From glucal 6, α-selectivity was also possible via a tran-
sition state such as TS-D (see Scheme 3). When galactal 8
was treated with propargyl alcohol (2a) under the same
conditions, the reaction was incomplete, even after three
hours (Scheme 4). Several factors might have influenced
the reactivity of 8; for instance, in the absence of the inter-
mediate C (see Scheme 3), the reaction would have needed
more time and/or a stronger Lewis acid to remove the ace-
tyl group from the 3-position.30,48 Consequently, the yields
were enhanced by using 100% (w/w of 8) of the 10% FeCl3-
loaded catalyst [MK10-(10% FeCl3∙6H2O)]. Two equivalents
of alcohol 2a, 2d, or 2g were found to be optimal to obtain
9a, 9d, and 9g in 69% (α/β = 5:1), 78% (α/β = 5:1), and 77%
(α/β = 5:1) yield, respectively. The α-selectivity from tri-O-
acetyl-D-galactal (8) might indicate that the presence of an
axial acetyl group in the 4-position (the position closest to
the C-1 atom) causes a bulk effect that helps to form a tran-
sition state such as D/D′.
Table 3 Attempts to Prepare Triazolyl Glucoside 10e
Entry
Conditions
Yield (%)
b
c
1
2
3
4
5
6
CuI, CH2Cl2, 24 h (AcOH/FeCl3)a
CuI, MeCN, 20 h (AcOH/FeCl3)a
CuI, Et3N, MeCN, 20 min (AcOH/FeCl3)a
CuI, MeCN
–
–
–
d
44e
CuI, Et3N, MeCN. 0.5 h
54f,g
CuI, MeCN, 12 h
78 (12.0)g,h
a In the presence of residual AcOH/FeCl3 from the glycosylation step.
b No reaction.
c Traces (20 h).
d Complex mixture (20 min).
e Yields for two steps. First step: glycosylation (10 min) followed by a leach-
ing procedure; second step: cycloaddition (12 h).
f 2-Amino-1,4-naphthoquinone was formed and substrate 5 was recov-
ered.
g Isolated yield.
h 5e (1.0 mmol) + 1 (0.75 mmol).
OBn
20%
We then tried a leaching procedure using a saturated
solution of sodium bicarbonate. After extraction, the sol-
vent was evaporated, and the residue was dissolved in ace-
tonitrile and treated with 2-azido-1,4-naphthoquinone in
the presence of 10 mol% of copper(I) iodide (Table 3, entry
4). The mixture was purified by column chromatography to
give glucoside 10e in 44% yield. For this reaction, with puri-
fication of 5e, the global yield was 62% after two steps.
Once the glycosylation step was complete, the cycload-
dition reaction was fast; treatment with copper(I) iodide
and triethylamine in acetonitrile at room temperature for
30 minutes gave 1H-1,2,3-triazol-4-yl glucoside 10e in 54%
yield (Table 3, entry 5). In the absence of triethylamine, 10e
in was obtained in 78% after 12 hours (entry 6). This is in
accord with our previous results.37 Furthermore, a mixture
of 1 mmol of glucoside 5e and 0.75 mmol of 2-azido-1,4-
naphthoquinone (1) showed better behavior than that
achieved with an excess of 1. On the basis of the good re-
sults that we obtained (entry 6), we synthesized 1H-1,2,3-
triazol-4-yl glucosides 10a–j by using copper(I) iodide in
acetonitrile at room temperature (Table 4). The reactions
were completed in 12 hours, giving 10a–j in yields of 62–
88%.
Scheme 5 shows our proposed mechanism. 2-Azido-
1,4-naphthoquinone (1) is an electron-deficient azide and,
consequently, more reactive, so the reaction can proceed
without base catalysis. On the other hand, this chemical
property also favors a copper-assisted decomposition via a
nitrene intermediate E after loss of a nitrogen molecule (D
→ E).47 Copper-assisted reduction might explain the forma-
tion of 2-amino-1,4-naphthoquinone via these intermedi-
ates. Apparently, in the presence of triethylamine, the re-
duction was faster than cycloaddition, resulting in the ob-
served increase in formation of the amino derivative under
basic conditions, and low yields of the cycloadduct. The re-
OBn
CH
O
[MK10-(5% FeCl3⋅6H2O)]
O
O
BnO
HO
BnO
OBn
2a (1.5 equiv)
7a (72%, α/β = 2:1)
6
OAc
100%
OAc
CH
O
[MK10-(10% FeCl3⋅6H2O)]
O
O
X
AcO
HO
X
2a,d,g (2 equiv)
AcO
OAc
9a (69%, α/β = 5:1)
9d (78%, α/β = 5:1)
9g (77%, α/β = 5:1)
8
Scheme 4 Synthesis of O-glycosides from glycals by using MK10/
FeCl3∙6H2O
With the 2,3-unsaturated alkynyl O-glucosides 5a–j in
hand, we focused on the synthesis of new 1H-1,2,3-triazol-
4-yl glucoside derivatives.
Attempts to promote a one-pot reaction, led to no ap-
preciable amounts of product (Table 3, entries 1–3). Initial-
ly, we attempted to perform the copper(I)-catalyzed azide–
alkyne cycloaddition immediately removal of the heteroge-
neous catalyst by filtration, even though acetic acid and
iron(III) chloride remained in the solution. When we subse-
quently added copper(I) iodide, no reaction was apparent
on TLC, even after prolonged reaction times (entry 1). In a
further attempt, we evaporated the dichloromethane after
the filtration step and then added copper(I) iodide and ace-
tonitrile, but only traces of the product were formed (entry
2). When triethylamine was used, a complex mixture was
obtained (entry 3).
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3535
V. N. Melo et al.
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Synthesis
action can proceed without a base via intermediates A and
B. The formation of 2-amino-1,4-naphthoquinone was also
observed, but in minor proportions.
We have described a simple and efficient method for
the synthesis of 2,3-unsaturated alkynyl O-glycosides by
using inexpensive and ecofriendly montmorillonite K-10
doped with iron(III) chloride hexahydrate as the catalyst.
This protocol provides glucosides 5a–j in good to excellent
yields (80–98%) and high α-anomeric stereoselectivity.
Other glycals such tri-O-benzyl-D-glucal or tri-O-acetyl-D-
galactal can be used as substrates for preparing O-glyco-
sides. Subsequently, we prepared the 1,2,3-1H-triazol-4-yl
Table 4 Synthesis of 1H-1,2,3-Triazol-4-yl Glucoside Derivatives 10a–j
Major product
Yielda (%) (α/β)b
73 (α only)
Major product
Yielda (%) (α/β)b
O
O
O
O
AcO
AcO
84 (–)c
N
N
O
N
N
O
AcO
AcO
O
O
N
N
10a
10f
O
O
O
AcO
AcO
N
O
N
N
N
N
82 (3:1)
83 (10:1)
O
O
O
N
AcO
O
AcO
10g
10b
OAc
O
O
O
O
OAc
AcO
O
62 (5:1)
86 (10:1)
78 (9:1)
78 (–)c
62 (–)c
83 (5:1)
N
N
N
N
O
O
O
O
N
N
AcO
O
10c
10h
OAc
OAc
O
O
O
O
AcO
O
N
N
N
AcO
N
N
N
O
10d
10i
OAc
AcO
AcO
O
O
O
O
AcO
O
O
N
N
N
N
N
N
O
10e
O
10j
a Isolated yield.
b Determined by 1H NMR.
c Not determined (complex diastereoisomeric mixture).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3529–3541

3536
V. N. Melo et al.
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Synthesis
copper-assisted azide reduction
[Cu]
O
O
[Cu]
N
O+
O+
N
N+
NH2
O
N
N3
– N2
Et3N+H
X
N
OR
O
O
O
2-amino-1,4-naphthoquinone
D
E
O
O
OAc
N
[Cu]
N
O
O
OAc
base-accelerated azide reduction
Et3N
C
X
H+
OAc
O
OAc
H
X
O
X
OR
H
[Cu]
N
+
O
A
[Cu]
N+
N
N–
O
O
N+
N
O
B
electron-deficient azide
OAc
O
OAc
copper-catalyzed azido-alkyne cycloaddition (CuAAC)
base/ligand free
R =
Scheme 5 Proposed mechanistic pathway for the formation of 1H-1,2,3-triazol-4-yl glucoside derivatives
glucoside derivatives 10a–j by means of a copper(I)-cata-
lyzed 1,3-dipolar cycloaddition. Despite our attempts, it
was not possible to develop a procedure for a one-pot syn-
thesis of the 1,2,3-triazoles; however, by leaching the reac-
tion mixture, a one-pot two-step procedure was per-
formed, with a global yield of 44%. Furthermore, we defined
a better strategy for preparing these target molecules for
future explorations of their biological profiles.
K-10/Iron(III) Chloride Catalyst [MK10/(5%FeCl3·6H2O)]
FeCl3∙6 H2O (50 mg) was mixed with montmorillonite K-10 (1 g) and
acetone (2 mL) in a round-bottomed flask. The mixture was homoge-
nized and the solvent was evaporated under reduced pressure.
Hydroxyalkyl-1,2,3-Triazoles (3b–d); General Procedure
The general procedure was adapted from that described in the litera-
ture.37 2-Azido-1,4-naphthoquinone (1; 1 mmol) and the appropriate
alkynol 2b–d (1.5 mmol) were mixed at 0 °C under argon in MeCN (2
mL). The mixture was then stirred at r.t. (25–30 °C) in the absence of
light for 12 h. The product was purified by flash column chromatog-
raphy [silica gel, hexane–EtOAc (6:4)].
All organic solvents were of analytical grade. Melting points were de-
termined in a capillary tube in a PFM II BioSan apparatus. Elemental
analyses were carried out by using an EA1110 CHNS-O analyzer. IR
spectra were recorded on an IFS66 Bruker spectrophotometer by us-
ing KBr discs. NMR spectra were obtained with a Varian Unity Plus-
300 spectrometer with CDCl3 as solvent, and were calibrated for the
solvent signal. Optical rotations were measured by using an Anton-
Paar model MCP200 polarimeter. Air- and moisture-sensitive reac-
tions were performed under an inert atmosphere of argon. The purifi-
cation was performed by column chromatography on Merck silica gel
60 (70–230 mesh). All reactions were monitored by TLC (GF-254).
Montmorillonite K-10 was purchased from Sigma-Aldrich. 2-Azido-
1,4-naphthoquinone (1),37 3,4,6-tri-O-acetyl-D-glucal (4), 3,4,6-tri-O-
acetyl-D-galactal (8),49 and 3,4,6-tri-O-benzyl-D-glucal (6)50 were pre-
pared by the reported procedures.
2-[4-(2-Hydroxyethyl)-1H-1,2,3-triazol-1-yl]-1,4-naphthoquinone
(3b)
Green solid; yield: 253 mg (94%); mp 119–121 °C; Rf = 0.1.
IR (KBr): 3277 (OH), 3184, 2927, 1677, 1655, 1615, 1593, 1294, 1224,
1051, 1017, 776, 716 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.10 (br s, 1 H, OH), 3.08 (t, J = 6.3 Hz, 2
H, CH2), 4.03 (t, J = 6.2 Hz, 2 H, CH2), 7.72 (s, 1 H, Hnaphth), 7.82–7.87
(m, 2 H, H-Ar), 8.14–8.21 (m, 2 H, H-Ar), 8.52 (s, 1 H, Htriaz).
13C NMR (75 MHz, CDCl3): δ = 28.7, 61.4, 123.9, 126.4, 126.5, 127.2,
131.0, 131.4, 134.4, 135.0, 139.4, 146.5, 179.4, 183.8.
Anal. Calcd for C14H11N3O3 (269.25): C, 62.45; H, 4.12. Found: C, 62.41;
H, 3.94.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3529–3541

3537
V. N. Melo et al.
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Synthesis
2-[4-(3-Hydroxypropyl)-1H-1,2,3-triazol-1-yl]-1,4-naphthoqui-
none (3c)
Colorless oil; yield: 260 mg (92%); Rf = 0.3; [α]D25 +130 (c 0.1, CH2Cl2)
[Lit.14 +91.3 (c 1.0, MeOH)].
Yellow solid; yield: 230 mg (81%); mp 118–120 °C; Rf = 0.1.
Pent-4-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-
enopyranoside (5c)
[CAS Reg. No. 1173831–41–8]44
Colorless oil; yield: 240 mg (81%); Rf = 0.6; [α]D25 +160 (c 0.1, CH2Cl2).
IR (KBr): 3410 (OH), 3183, 2961, 2935, 1678, 1654, 1623, 1586, 1298,
1262, 1055, 790, 718 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.81 (br s, 1 H, OH), 2.03 (q, J = 6.6 Hz,
2 H, CH2), 2.95 (t, J = 7.2 Hz, 2 H, CH2), 3.76 (t, J = 6.3 Hz, 2 H, CH2), 7.74
(s, 1 H, Hnaphth), 7.83–7.87 (m, 2 H, H-Ar), 8.14–8.22 (m, 2 H, H-Ar),
8.44 (s, 1 H, Htriaz).
IR (KBr): 3283, 2934, 2092 (C≡C), 1743 (C=O), 1435, 1371, 1231, 1033
c m–1
.
13C NMR (75 MHz, CDCl3): δ = 21.9, 31.8, 61.8, 123.2, 126.3, 126.6,
127.2, 131.1, 131.5, 134.4, 135.0, 139.4, 148.6, 179.5, 183.9.
Hex-5-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-
enopyranoside (5d)
Colorless oil; yield: 304 mg (98%); Rf = 0.4; [α]D25 +140 (c 0.1, CH2Cl2).
Anal. Calcd for C15H13N3O3 (283.28): C, 63.60; H, 4.63. Found: C, 63.66;
H, 4.24.
IR (KBr): 3288, 2942, 2092 (C≡C), 1745 (C=O), 1371, 1239, 1041 cm–1
.
2-[4-(3-Hydroxybutyl)-1H-1,2,3-triazol-1-yl]-1,4-naphthoqui-
none (3d)
1H NMR (300 MHz, CDCl3): δ = 1.59–1.65 (m, 2 H, CH2), 1.72–1.75 (m,
2 H, CH2), 1.96 (t, J = 2.7 Hz, 1 H, CH), 2.09 (s, 3 H, CH3CO), 2.11 (s, 3 H,
CH3CO), 2.24 (td, J = 7.0, 2.7 Hz, 2 H, CH2), 3.55 (dt, J = 9.8, 5.8 Hz, 1 H,
CH2), 3.81 (dt, J = 9.8, 6.2 Hz, 1 H, CH2), 4.10 (ddd, J = 9.8, 5.5, 2.4 Hz, 1
H, H-5), 4.19 (dd, J = 12.1, 2.7 Hz, 1 H, H-6), 4.25 (dd, J = 12.1, 5.4 Hz, 1
H, H-6′), 5.03 (br s, 1 H, H-1), 5.31 (ddd, J = 9.8, 2.7, 1.5 Hz, 1 H, H-4),
5.83 (ddd, J = 10.2, 2.3, 1.5 Hz, 1 H, H-2), 5.89 (dd, J = 10.6, 1.2 Hz, 1 H,
H-3).
Green solid; yield: 244 mg (82%); mp 99–101 °C; Rf = 0.2.
IR (KBr): 3351 (OH), 3165, 2926, 2852, 1678, 1653, 1614, 1590, 1298,
1331, 1295, 1051, 717 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.69 (q, J = 6.6 Hz, 2 H, CH2), 1.86 (q, J =
7.8 Hz, 2 H, CH2), 1.95 (br s, 1 H, OH), 2.86 (t, J = 7.8 Hz, 2 H, CH2), 3.71
(t, J = 6.2 Hz, 2 H, CH2), 7.72 (s, 1 H, Hnaphth), 7.80–7.86 (m, 2 H, H-Ar),
8.13–8.20 (m, 2 H, H-Ar), 8.41 (s, 1 H, Htriaz).
13C NMR (75 MHz, CDCl3): δ = 18.1, 20.8, 21.0, 25.2, 28.7, 63.1, 65.3,
66.9, 68.2, 68.6, 84.1, 94.4, 127.8, 129.0, 170.3, 170.8.
13C NMR (75 MHz, CDCl3): δ = 25.2, 25.3, 32.0, 62.4, 123.0, 126.1,
Anal. Calcd for C16H22O6 (310.34): C, 61.92; H, 7.15. Found: C, 62.26;
H, 7.49.
126.5, 127.2, 131.1, 131.4, 134.3, 134.9, 139.4, 149.1, 179.4, 183.9.
Anal. Calcd for C16H15N3O3 (297.30): C, 64.64; H, 5.09. Found: C, 64.90;
H, 5.33.
1,1-Dimethylprop-2-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (5e)
[CAS Reg. No. 1400767–35–2]14
2,3-Unsaturated Alkynyl O-Glycosides 5a–j, 7a, 9a, 9d, and 9g; Gen-
eral Procedures
Colorless oil; yield: 237 mg (80%); Rf = 0.4; [α]D25 +170 (c 0.1, CH2Cl2)
[Lit.14 +51.7 (c 0.5, MeOH)].
Method A. To a solution of tri-O-acetyl-D-glucal (4; 1 mmol) in CH2Cl2
(2 mL; dried with CaCl2) at 0 °C was added MK10-(5% FeCl3·6 H2O) (20
wt% w.r.t. 4; 54.4 mg or 0.01 mmol FeCl3). The appropriate alcohol
(1.5 mmol) was then added.
IR (KBr): 3276, 2922, 2074 (C≡C), 1740 (C=O), 1438, 1368, 1228, 1026
cm–1
.
Method B. To a solution of tri-O-benzyl-D-glucal 6 (83 mg, 0.2 mmol)
in CH2Cl2 (2 mL; dried with CaCl2) at 0 °C was added MK10-(5%
FeCl3·6 H2O) (20 wt% w.r.t. 6; 17 mg or 0.003 mmol FeCl3). The appro-
priate alcohol (0.3 mmol, 1.5 equiv) was then added
(R,S)-1-Methylprop-2-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (5f)
[CAS Reg. No. 1192736–23–4]15
Method C. To a solution of tri-O-acetyl-D-galactal 8 (100 mg, 0.37
mmol) in CH2Cl2 (2 mL; dried with CaCl2) at 0 °C was added MK10-
(10% FeCl3·6 H2O) (100 wt% w.r.t. 8; 100 mg or 0.02 mmol FeCl3). The
appropriate alcohol (0.74 mmol, 2 equiv) was then added.
Colorless oil; yield: 268 mg (95%), (Lit.15 72%); Rf = 0.3 (hexane–EtOAc,
8:2); [α]D25 +90 (c 0.1, CH2Cl2).
IR (KBr): 3270, 2933, 2110 (C≡C), 1740 (C=O), 1439, 1371, 1229, 1034
cm–1
.
Workup. The mixture was refluxed for 10 min. Removal of the catalyst
by filtration and evaporation of the solvent under vacuum gave a resi-
due that was purified by flash column chromatography [silica gel,
hexane–EtOAc (7:3; 50 mL)].
The 1H and 13C NMR data are for a mixture rich in one diastereomer
(2:1) after a second slow column chromatographic purification.
1H NMR (300 MHz, CDCl3): δ = 1.47 (d, J = 7.0 Hz, 3 H, CH3), 2.07 (s, 3
H, CH3CO), 2.08 (s, 3 H, CH3CO), 2.44 (d, J = 2.4 Hz, 1 H, CH), 4.06 (ddd,
J = 9.8, 5.9, 2.7 Hz, 1 H, H5), 4.17–4.22 (m, 2 H, H-6 and H-6′), 4.55 (dq,
J = 6.9, 2.0 Hz, 1 H, CHO), 5.31 (ddd, J = 9.8, 3.1, 1.6 Hz, 1 H, H-4), 5.37
(br s, 1 H, H-1), 5.83 (ddd, J = 10.4, 1.5, 1.5 Hz, 1 H, H-2), 5.90 (br d, J =
10.2 Hz, 1 H, H-3).
Prop-2-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-
enopyranoside (5a)
[CAS Reg. No. 121237–62–5]14,15,29
White solid; yield: 249 mg (93%); mp 55–57 °C (Lit.15 56–58 °C); Rf =
0.3; [α]D25 +170 (c 0.1, CH2Cl2) [Lit.29 +156.4 (c 1.0, CH3Cl)].
13C NMR (75 MHz, CDCl3): δ = 20.7, 20.9, 22.0, 62.0, 63.0, 65.3, 67.2,
73.5, 82.8, 91.7, 127.7, 129.4, 170.2, 170.7.
IR (KBr): 3279, 2904, 2110 (C≡C), 1739 (C=O), 1377, 1237, 1042 cm–1
.
1-Ethynylcyclohexyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-
hex-2-enopyranoside (5g)
Colorless oil; yield: 289 mg (86%); Rf = 0.5; [α]D25 +140 (c 0.1, CH2Cl2).
But-3-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-eno-
pyranoside (5b)
[CAS Reg. No. 135195–22–1]14
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3538
V. N. Melo et al.
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Synthesis
IR (KBr): 3272, 2937, 2860, 2060 (C≡C), 1745 (C=O), 1450, 1371, 1236,
1031 cm–1
IR (KBr): 3277, 2975, 2941, 2074 (C≡C), 1746 (C=O), 1372, 1238, 1028
.
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.24–1.90 (m, 10 H, 5CH2), 2.08 (s, 6 H,
2CH3CO), 2.57 (s, 1 H, CH), 4.14–4.25 (m, 3 H, H-5, H-6, and H-6′), 5.28
(d, J = 8.6 Hz, 1 H, H-4), 5.73 (br s, 1 H, H-1), 5.80 (br d, J = 10.6 Hz, 1 H,
H-2), 5.87 (br d, J = 10.5 Hz, 1 H, H-3).
13C NMR (75 MHz, CDCl3): δ = 20.8, 22.9, 25.2, 38.6, 63.2, 65.2, 67.2,
75.1, 84.4, 90.7, 128.4, 129.1, 170.3, 170.8.
1H NMR (300 MHz, CDCl3): δ = 0.96 (t, J = 7.1 Hz, 3 H, CH3), 0.97 (t, J =
7.6 Hz, 3 H, CH3), 1.65–1.73 (m, 2 H, CH2), 1.80–1.94 (m, 2 H, CH2),
2.07 (s, 6 H, 2 × CH3CO), 2.56 (s, 1 H, CH), 4.10–4.16 (m, 2 H, H-5 and
H-6), 4.23 (dd, J = 12.5, 5.9 Hz, 1 H, H-6′), 5.27 (ddd, J = 9.4, 2.9, 1.8 Hz,
1 H, H-4), 5.65 (br s, 1 H, H-1), 5.78 (ddd, J = 10.0, 2.9, 1.8 Hz, 1 H, H-
2), 5.86 (br d, J = 10.6 Hz, 1 H, H-3).
13C NMR (75 MHz, CDCl3): δ = 8.3, 8.4, 20.7, 20.8, 31.7, 32.4, 34.2, 62.9,
63.2, 65.2, 67.2, 83.4, 90.9, 128.3, 128.9, 170.3, 170.9.
Anal. Calcd for C18H24O6 (336.38): C, 64.27; H, 7.19. Found: C, 64.65;
H, 7.50.
Anal. Calcd for C17H24O6 (324.37): C, 62.95; H, 7.46. Found: C, 62.98;
H, 7.77.
(R,S)-1-Isobutylprop-2-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (5h)
Colorless oil; yield: 292 mg (90%); Rf = 0.6; [α]D25 +180 (c 0.1, CH2Cl2).
Prop-2-yn-1-yl 4,6-Di-O-benzyl-2,3-dideoxy-α-D-erythro-hex-2-
enopyranoside (7a)
[CAS Reg. No. 251914–74–6]51,52
Colorless oil; yield: 54 mg (72%, α/β = 2:1); (Lit.51 74% α/β = 8:1); Rf =
0.5 (hexane–EtOAc, 8:2); [α]D25 +69.8 (c 0.3, CH2Cl2) [Lit.52 +158 (c 2.7,
CH3Cl)].
IR (KBr): 3274, 2958, 2936, 2093 (C≡C), 1745 (C=O), 1370, 1236, 1028
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.90–0.95 (m, 12 H, 4CH3, R/S), 1.52–
1.62 (m, 2 H, CH, R/S), 1.67–1.76 (m, 2 H, CH2, R/S), 1.80–1.90 (m, 2 H,
CH2, R or S), 2.06–2.08 (m, 12 H, 4CH3CO, R/S), 2.42 (d, J = 2.0 Hz, 1 H,
CH, R or S), 2.44 (d, J= 2.0 Hz, 1 H, CH, R or S), 4.04 (ddd, J = 9.4, 5.5, 2.4
Hz, 2 H, H-5, R/S), 4.15–4.25 (m, 4 H, H-6 and H-6′, R/S), 4.31–4.36 (m,
1 H, CHO, R or S), 4.49–4.53 (m, 1 H, CHO, R or S), 5.16 (br s, 1 H, H-1,
R or S), 5.27–5.30 (m, 2 H, H-4, R/S), 5.40 (br s, 1 H, H-1, R or S), 5.77–
5.83 (m, 2 H, H-2, R/S), 5.89 (br d, J = 10.1 Hz, 2 H, H-3, R/S).
Prop-2-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-threo-hex-2-eno-
pyranoside (9a)
[CAS Reg. No. 158053–95–3]15,51
Colorless oil; yield: 68 mg (69%, α/β = 5:1) (Lit.51 75%, α/β = 19:1);
[α]D25 –101.4 (c 0.7, CH2Cl2) [Lit.15 –107.9 (c 0.5, CHCl3)].
13C NMR (75 MHz, CDCl3): δ = 20.7, 20.9, 21.9, 22.5, 22.7, 24.4, 44.4,
44.8, 62.4, 63.1, 64.5, 64.9, 65.2, 67.2, 72.9, 73.9, 82.4, 91.3, 94.6,
127.3, 127.7, 129.1, 129.5, 170.1, 170.2, 170.7, 170.8.
Hex-5-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-threo-hex-2-eno-
Anal. Calcd for C17H24O6 (324.37): C, 62.95; H, 7.46. Found: C, 63.32;
H, 7.22.
pyranoside (9d)
Colorless oil; yield: 89 mg (78%, α/β = 5:1); Rf = 0.6; [α]D25 –79.6 (c 0.2,
CH2Cl2).
(R,S)-1-Phenylprop-2-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (5i)
1H NMR (300 MHz, CDCl3): δ = 1.59–1.65 (m, 2 H, CH2), 1.70–1.79 (m,
2 H, CH2), 1.96 (t, J = 3.0 Hz, 1 H, C≡CH), 2.08 (br s, 6 H, 2 × CH3CO),
2.24 (td, J = 7.0, 2.9 Hz, 2 H, CH2), 3.54 (dt, J = 9.4, 6.5 Hz, 1 H, CH2),
3.82 (dt, J = 9.9, 6.5 Hz, 1 H, CH2), 4.21–4.24 (m, 2 H, H-6 and H-6′),
4.35 (ddd, J = 7.6, 5.8, 2.9 Hz, 1 H, H-5), 5.02 (dd, J = 5.2, 2.4 Hz, 1 H, H-
4), 5.07 (d, J = 2.9 Hz, 1 H, H-1), 6.03 (dd, J = 10.0, 3.0 Hz, 1 H, H-2),
6.12 (dd, J = 10.0, 4.7 Hz, 1 H, H-3).
[CAS Reg. No. 957636–17–8] (No data).
Yellow oil; yield: 334 mg (97%); Rf = 0.6; [α]D25 +80 (c 0.1, CH2Cl2).
IR (KBr): 3289, 2923, 2129 (C≡C), 1739 (C=O), 1454, 1372, 1239, 1022,
947, 738, 699, 645 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.01–2.14 (m, 12 H, 2 × CH3CO, R/S),
2.65 (d, J = 2.3 Hz, 1 H, CH, R or S), 2.68 (d, J = 1.9 Hz, 1 H, CH, R or S),
4.11–4.31 (m, 6 H, H-5, H-6 and H-6′, R/S), 5.08 (d, J = 2.0 Hz, 1 H, H-1,
R or S), 5.33–5.39 [m, 2 H (H-4, R or S; H-1, R or S)], 5.47 (dd, J = 10.1,
2.0 Hz, 1 H, H-4, R or S), 5.57 (br s, 2 H, CHO, R/S), 5.71–5.94 (m, 4 H,
H-2 and H-3, R/S), 7.35–7.42 (m, 6 H, HAr), 7.50–7.57 (m, 4 H, ortho-
HAr).
13C NMR (75 MHz, CDCl3): δ = 18.1, 20.8 (2 C), 25.2, 28.6, 62.8, 62.9,
66.8, 67.8, 68.6, 84.1, 93.8, 125.1, 130.6, 170.4, 170.6.
Anal. Calcd for C16H22O6 (310.34): C, 61.92; H, 7.15. Found: C, 62.35;
H, 7.47.
1-Ethynylcyclohexyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-threo-hex-2-
enopyranoside (9g)
13C NMR (75 MHz, CDCl3): δ = 20.8 (2 C), 20.9 (2 C), 62.6, 63.1, 65.1,
65.3, 67.3, 67.4, 68.3, 69.0, 74.8, 75.1, 76.2, 80.7, 82.1, 91.9, 92.4,
126.6, 127.3, 127.5 (2 C), 127.6, 127.8, 128.5, 128.6, 128.7 (3 C), 128.9,
129.6, 129.8, 137.6, 137.7, 170.2, 170.3, 170.7, 170.8.
25
Yellow oil; yield: 95 mg (77%, α/β = 5:1); Rf = 0.6; [α]D –38.1 (c 0.4,
CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 1.53–1.71 (m, 10 H, 5CH2), 2.05 (s, 3 H,
2CH3CO), 2.07 (s, 3 H, 2CH3CO), 2.48 (s, 1 H, CH), 4.20–4.22 (m, 2 H, H-
6 and H-6′), 4.42 (ddd, J = 6.5, 6.5, 2.4 Hz, 1 H, H-5), 5.03 (dd, J = 5.9,
3.0 Hz, 1 H, H-4), 5.79 (br d, J = 2.9 Hz, 1 H, H-1), 5.99 (dd, J = 10.0, 3.5
Hz, 1 H, H-2), 6.12 (dd, J = 9.9, 2.9 Hz, 1 H, H-3).
Anal. Calcd for C19H20O6 (344.36): C, 66.27; H, 5.85. Found: C, 66.58;
H, 5.47.
1,1-Diethylprop-2-yn-1-yl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-eryth-
ro-hex-2-enopyranoside (5j)
13C NMR (75 MHz, CDCl3): δ = 20.7, 23.0, 25.1, 25.2, 38.7, 62.8 (2 C),
Colorless oil; yield: 291 mg (90%); Rf = 0.7; [α]D25 +100 (c 0.1, CH2Cl2).
67.0, 72.1, 75.4, 84.3, 90.3, 124.6, 131.8, 170.4, 170.6.
Anal. Calcd for C18H24O6 (336.38): C, 64.27; H, 7.19. Found: C, 64.01;
H, 7.34.
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Synthesis
1H-1,2,3-Triazol-1-yl Glucoside Derivatives 10a–j; General Proce-
[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-4-
dure
yl]butyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyra-
noside (10d)
2-Azido-1,4-naphthoquinone (1; 0.75 mmol) was added to a solution
of the appropriate 2,3-unsaturated alkynyl O-glucoside 5a–j (1 mmol)
and CuI (10 mol%, 0.1 mmol) in MeCN (2 mL) at 0 °C, and the mixture
was stirred at r.t. (25–30 °C) for 12 h. Because of their proximity to 2-
amino-1,4-naphthoquinone on TLC, the products was purified by
two-step column chromatography [silica gel, hexane–EtOAc (6:4, 100
mL) then CH2Cl2–EtOAc (9:1, 100 mL)].
Green solid; yield: 438 mg (86%); mp 74–75 °C; Rf = 0.3 (hexane–
EtOAc, 7:3); [α]D25 +70 (c 0.1, CH2Cl2).
IR (KBr): 3162, 3071, 2926, 2866, 1732, 1677, 1654, 1373, 1238, 1017,
985 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.74 (m, 2 H, CH2), 1.87 (m, 2 H, CH2),
2.08 (s, 3 H, CH3CO), 2.10 (s, 3 H, CH3CO), 2.87 (t, J = 7.5 Hz, 2 H, CH2),
3.57 (dt, J = 9.8, 6.2 Hz, 1 H, CH2O), 3.85 (dt, J = 9.8, 6.3 Hz, 1 H, CH2O),
4.11 (ddd, J = 9.4, 5.5, 2.4 Hz, 1 H, H-5), 4.18 (dd, J = 11.7, 2.3 Hz, 1 H,
H-6), 4.25 (dd, J = 12.1, 5.5 Hz, 1 H, H-6′), 5.04 (br s, 1 H, H-1), 5.32
(ddd, J = 9.8, 2.7, 1.6 Hz, 1 H, H-4), 5.84 (ddd, J = 10.2, 2.4, 1.6 Hz, 1 H,
H-2), 5.89 (dd, J = 10.5, 1.2 Hz, 1 H, H-3), 7.75 (s, 1 H, Hnaphth), 7.83–
7.86 (m, 2 H, Hnaphth), 8.15–8.18 (m, 1 H, Hnaphth), 8.20–8.22 (m, 1 H,
[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-4-
yl]methyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopy-
ranoside (10a)
[CAS Reg. No. 1353244–67–3]37
Yellow solid; yield: 341 mg (73%); mp 115 °C (Lit.37 108–110 °C);
[α]D25 +70 (c 0.1, CH2Cl2) [Lit.31 +56 (c 0.4, CH3Cl)].
H
naphth), 8.42 (s, 1 H, Htriaz).
13C NMR (75 MHz, CDCl3): δ = 20.8, 21.0, 25.3, 25.9, 29.2, 63.0, 65.3,
66.9, 68.4, 94.4, 123.0, 126.1, 126.5, 127.2, 127.8, 129.0, 131.1, 131.5,
134.3, 135.0, 139.4, 149.0, 170.3, 170.8, 179.5, 183.9.
IR (KBr): 3165, 3073, 2944, 1745, 1677, 1655, 1372, 1233, 1032, 972
cm–1
.
[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-4-
yl]ethyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyra-
noside (10b)
Anal. Calcd for C26H27N3O8 (509.51): C, 61.29; H, 5.34. Found: C, 61.38;
H, 5.45.
Green solid; yield: 394 mg (82%); mp 76–78 °C; Rf = 0.23 (hexane–
EtOAc, 7:3); [α]D25 +100 (c 0.1, CH2Cl2).
[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-4-yl]-
1-methylethyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-en-
opyranoside (10e)
1H NMR (300 MHz, CDCl3): δ = 2.08 (s, 3 H, CH3CO), 2.10 (s, 3 H, CH3-
CO), 3.17 (t, J = 6.5 Hz, 2 H, CH2), 3.88 (dt, J = 13.1, 6.4 Hz, 2 H, CH2O),
4.10–4.26 (m, 3 H, H-5, H-6, H-6′), 5.10 (br s, 1 H, H-1), 5.33 (d, J = 9.9
Hz, 1 H, H-4), 5.86 (dd, J = 9.8, 2.0 Hz, 1 H, H-2), 5.91 (br d, J = 10.5 Hz,
1 H, H-3), 7.76 (s, 1 H, Hnaphth), 7.81–7.89 (m, 2 H, Hnaphth), 8.15–8.18
(m, 1 H, Hnaphth), 8.20–8.23 (m, 1 H, Hnaphth), 8.51 (s, 1 H, Htriaz).
13C NMR (75 MHz, CDCl3): δ = 20.8, 21.0, 26.5, 63.0, 65.3, 67.1, 67.3,
94.6, 123.9, 126.3, 126.6, 127.2, 127.5, 129.3, 131.1, 131.5, 134.3,
135.0, 139.4, 146.1, 170.2, 170.8, 179.4, 183.8.
25
Yellow oil; yield: 387 mg (78%); Rf = 0.3 (hexane–EtOAc, 6:4); [α]D
+130 (c 0.1, CH2Cl2).
IR (KBr): 2981, 2930, 1742, 1682, 1664, 1370, 1297, 1240, 1026 cm–1
.
1H NMR (300MHz, CDCl3): δ = 1.77 (s, 3 H, CH3), 1.82 (s, 3 H, CH3),
2.08 (s, 3 H, CH3CO), 2.09 (s, 3 H, CH3CO), 4.10–4.13 (m, 1 H, H-5),
4.16–4.23 (m, 2 H, H-6 and H-6′), 5.23 (br s, 1 H, H-1), 5.27 (br d, J =
9.4 Hz, 1 H, H-4), 5.77 (ddd, J = 10.2, 1.9, 1.9 Hz, 1 H, H-2), 5.88 (br d,
J = 10.2 Hz, 1 H, H-3), 7.78 (s, 1 H, Hnaphth), 7.85–7.87 (m, 2 H, Hnaphth),
8.17–8.19 (m, 1 H, Hnaphth), 8.21–8.23 (m, 1 H, Hnaphth), 8.60 (s, 1 H,
Anal. Calcd for C24H23N3O8 (481.45): C, 59.87; H, 4.82. Found: C, 60.20;
H, 4.90.
H
triaz).
13C NMR (75 MHz, CDCl3): δ = 20.8, 21.0, 27.2, 28.9, 63.0, 65.2, 67.0,
74.1, 89.9, 123.2, 126.6 (2 C), 127.2, 128.7, 128.8, 131.5, 134.4, 135.0,
139.3, 153.8, 170.3, 170.8, 179.4, 183.8.
[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-4-
yl]propyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopy-
ranoside (10c)
Anal. Calcd for C25H25N3O8 (495.48): C, 60.60; H, 5.09. Found: C, 60.27;
H, 5.55.
Yellow solid; yield: 307 mg (62%); mp 50–52 °C; Rf = 0.1 (hexane–
EtOAc, 7:3); [α]D25 +120 (c 0.1, CH2Cl2).
IR (KBr): 3165, 3076, 2949, 1738, 1678, 1655, 1374, 1228, 1018, 976
(R,S)-1-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-tri-
azol-4-yl]ethyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-
enopyranoside (10f)
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.07 (s, 3 H, CH3CO), 2.08 (s, 3 H,
CH3CO), 2.11–2.07 (m, 2 H, CH2) 2.93 (td, J = 7.6, 2.3 Hz, 2 H, CH2), 3.60
(dt, J = 11.7, 5.8 Hz, 1 H, CH2O), 3.88 (dt, J = 12.9, 6.4 Hz, 1 H, CH2O),
4.12 (ddd, J = 12.3, 5.3, 2.3 Hz, 1 H, H-5), 4.17 (dd, J = 11.2, 2.3 Hz, 1 H,
H-6), 4.25 (dd, J= 11.8, 5.8 Hz, 1 H, H-6′), 5.05 (br s, 1 H, H-1), 5.31 (d,
J = 11.8 Hz, 1 H, H-4), 5.87–5.96 (m, 2 H, H-2 and H-3), 7.73 (s, 1 H,
Green solid; yield 404 mg (84%); mp 94–96 °C; Rf = 0.5 (hexane–
EtOAc, 6:4); [α]D25 +90 (c 0.1, CH2Cl2).
IR (KBr): 3155, 2944, 1737, 1681, 1622, 1372, 1241, 1017 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.67 (d, J = 6.6 Hz, 3 H, CH3, R or S), 1.71
(d, J = 6.7 Hz, 3 H, CH3, R or S), 2.04 (s, CH3CO, R or S) 2.07 (s, 3 H,
CH3CO, R or S), 2.10 (s, 3 H, CH3CO, R or S), 2.14 (s, 3 H, CH3CO, R or S),
4.03 (dd, J = 12.1, 2.3 Hz, 1 H, H-6, R or S), 4.07–4.14 (m, 2 H, H-5, R/S),
4.17–4.32 [m, 5 H (H-6, R or S; H-6′, R/S; CHO, R/S)], 5.22 (br s, 1 H, H-
1, R or S), 5.23 (br s, 1 H, H-1, R or S), 5.33–5.36 (m, 2 H, H-4, R/S),
H
naphth), 7.81–7.85 (m, 2 H, Hnaphth), 8.13–8.16 (m, 1 H, Hnaphth), 8.18–
8.21 (m, 1 H, Hnaphth), 8.43 (s, 1 H, Htriaz).
13C NMR (75 MHz, CDCl3): δ = 20.7, 20.9, 22.3, 29.1, 63.0, 65.2, 66.9,
67.8, 94.4, 123.0, 126.1, 126.5 (2 C), 127.2, 127.7, 129.1, 131.1, 134.3,
135.0, 139.3, 148.5, 170.2, 170.7, 179.5, 183.8.
5.81–5.94 (m, 4 H, H-2 and H-3, R/S), 7.76 and 7.77 (2 × s, 2 H, Hnaphth
,
R/S), 7.84–7.87 (m, 4 H, Hnaphth, R/S), 8.16–8.23 (m, 4 H, Hnaphth, R/S),
8.61 (s, 2 H, Htriaz, R/S).
Anal. Calcd for C25H25N3O8 (495.48): C, 60.60; H, 5.09. Found: C, 60.49;
H, 5.26.
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3540
V. N. Melo et al.
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Synthesis
13C NMR (75 MHz, CDCl3): δ = 20.0, 20.8, 21.0, 21.8, 62.6, 63.1, 65.2,
65.4, 67.0, 67.2, 68.1, 92.7, 93.0, 110.0, 123.2, 123.4, 126.6, 127.2,
127.6, 127.7, 129.3, 129.6, 131.0, 131.4, 134.4, 135.0, 135.1, 139.2,
150.7, 170.2, 170.8, 179.3, 183.7.
(d, J = 7.1 Hz, 4 H, ortho-HAr, R/S), 7.74 (s, 1 H, Hnaphth, R or S), 7.76 (s, 1
H, Hnaphth, R or S), 7.81–7.88 (m, 4 H, Hnaphth, R or S), 8.15–8.20 (m, 4 H,
H
naphth, R or S), 8.44 (s, 1 H, Htriaz, R or S), 8.48 (s, 1 H, Htriaz, R or S).
13C NMR (75 MHz, CDCl3): δ = 20.7, 20.9, 21.0 (2 C), 62.5, 62.9, 65.2,
65.3, 67.3, 73.0, 74.0, 91.8, 93.8, 110.0, 124.1, 124.3, 126.5, 126.6,
126.7, 126.9, 127.1, 127.2, 127.4, 127.5, 128.2, 128.3, 128.6, 128.8,
128.9, 129.8, 131.0, 131.4, 134.4 (2 C), 135.0, 135.1, 140.1, 170.2,
170.4, 179.2, 183.7.
Anal. Calcd for C24H23N3O8 (481.45): C, 59.87; H, 4.82. Found: C, 60.01;
H, 4.73.
1-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-4-
yl]cyclohexyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-eno-
pyranoside (10g)
Anal. Calcd for C29H25N3O8 (543.52): C, 64.08; H, 4.64. Found: C, 63.71;
H, 4.76.
25
Yellow oil; yield: 445 mg (83%); Rf = 0.3 (hexane–EtOAc, 7:3); [α]D
+100 (c 0.1, CH2Cl2).
1-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-4-
yl]-1-ethylpropyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-
enopyranoside (10j)
1H NMR (300 MHz, CDCl3): δ = 1.42–1.87 (m, 10 H, H-cyclohexyl),
2.06 (s, 3 H, CH3CO), 2.08 (s, 3 H, CH3CO), 4.07 (dd, J = 11.8, 1.6 Hz, 1 H,
H-6), 4.13–4.23 (m, 2 H, H-5 and H-6′), 5.10 (br s, 1 H, H-1), 5.24 (br d,
J = 9.4 Hz, 1 H, H-4), 5.70 (ddd, J = 10.2, 1.9, 1.9 Hz, 1 H, H-2), 5.84 (br
d, J = 10.2 Hz, 1 H, H-3), 7.78 (s, 1 H, Hnaphth), 7.85–7.87 (m, 2 H,
25
Yellow oil; yield: 435 mg (83%); Rf = 0.4 (hexane–EtOAc, 6:4); [α]D
+70 (c 0.1, CH2Cl2).
IR (KBr): 2968, 2930, 1742, 1663, 1593, 1457, 1370, 1237, 1007 cm–1
.
H
naphth), 8.16–8.22 (m, 2 H, Hnaphth), 8.63 (s, 1 H, Htriaz).
1H NMR (300 MHz, CDCl3): δ = 0.81–0.93 (m, 6 H, CH3), 2.07 (s, 3 H,
CH3CO), 2.10 (s, 3 H, CH3CO), 2.11–2.23 (m, 4 H, CH2), 4.13 (dd, J =
13.7, 4.5 Hz, 1 H, H-6), 4.18–4.28 (m, 2 H, H-5 and H-6′), 5.20 (br s, 1
H, H-1), 5.27 (br d, J = 11.5 Hz, 1 H, H-4), 5.77 (ddd, J = 10.2, 2.1, 2.1
Hz, 1 H, H-2), 5.88 (br d, J = 10.5 Hz, 1 H, H-3), 7.79 (s, 1 H, Hnaphth),
7.83–7.89 (m, 2 H, Hnaphth), 8.16–8.22 (m, 2 H, Hnaphth), 8.61 (s, 1 H,
13C NMR (75 MHz, CDCl3): δ = 20.8, 21.0, 21.9, 22.3, 25.4, 35.4, 36.7,
37.9, 62.9, 65.1, 67.2, 75.5, 89.8, 124.1, 126.5, 126.6, 127.2, 128.3,
128.9, 131.1, 131.5, 134.4, 135.0, 139.3, 170.3, 170.7, 179.4, 183.8.
Anal. Calcd for C28H29N3O8 (535.55): C, 62.80; H, 5.46. Found: C, 62.74;
H, 5.45.
H
triaz).
13C NMR (75 MHz, CDCl3): δ = 7.7, 7.9, 20.8, 21.0, 28.3, 29.8, 62.9, 65.0,
67.4, 80.5, 89.4, 124.6, 126.4, 126.6, 127.2, 128.5, 128.8, 131.1, 131.5,
134.4, 135.0, 139.3, 152.0, 170.3, 170.7, 179.5, 183.8.
(R,S)-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-
4-yl]-3-methylbutyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-
2-enopyranoside (10h)
25
Brown oil; yield: 408 mg (78%); Rf = 0.6 (hexane–EtOAc, 6:4); [α]D
Anal. Calcd for C27H29N3O8 (523.53): C, 61.94; H, 5.58. Found: C, 62.15;
H, 5.66.
+110 (c 0.1, CH2Cl2).
IR (KBr): 2969, 2925, 1742, 1682, 1664, 1370, 1239, 1016 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.82–0.90 (m, 12 H, 4 × CH3, R/S), 2.07
(s, 6 H, 2 × CH3CO, R/S), 2.10 (s, 6 H, CH3CO, R/S), 2.12–2.25 (m, 8 H,
CH2, CH, CHO, R/S), 4.10–4.15 (m, 2 H, H-6, R/S), 4.18–4.23 (m, 4 H, H-
5 and H-6′, R/S), 5.20 (br s, 2 H, H-1, R/S), 5.27 (d, J = 8.6 Hz, 2 H, H-4,
R/S), 5.78 (ddd, J = 10.2, 2.0, 2.0 Hz, 2 H, H-2, R/S), 5.88 (br d, J = 10.2
Acknowledgment
The authors are grateful to CNPq (448082/2014-4) and FACEPE-
PRONEM for financial support. V.N.eM. thanks CAPES for a fellowship.
Our thanks are also extended to the analytical centers CENAPESQ-
UFRPE and DQF-UFPE.
Hz, 2 H, H-3, R/S), 7.78 (s, 2 H, Hnaphth, R/S), 7.83–7.88 (m, 4 H, Hnaphth
R/S), 8.16–8.22 (m, 4 H, Hnaphth, R/S), 8.61 (s, 2 H, Htriaz, R/S).
,
13C NMR (75 MHz, CDCl3): δ = 7.7, 7.8, 20.8, 21.0, 28.3, 29.8, 62.9, 65.0,
67.4, 80.5, 89.4, 110.0, 124.6, 126.4, 126.6, 127.2, 128.5, 128.8, 131.1,
131.5, 134.4, 135.0, 139.3, 152.0, 170.3, 170.8, 179.4, 183.8.
Supporting Information
Supporting information for this article is available online at
Anal. Calcd for C27H29N3O8 (523.53): C, 61.94; H, 5.58. Found: C, 61.55;
H, 5.53.
http://dx.doi.org/10.1055/s-0034-1378829.
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rmoaitn
(R,S)-[1-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazol-
4-yl](phenyl)methyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-
2-enopyranoside (10i)
References
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Green solid; yield: 337 mg (62%); mp 58–60 °C; Rf = 0.5 (hexane–
EtOAc, 6:4); [α]D25 +50 (c 0.1, CH2Cl2).
IR (KBr): 3065, 2926, 2856, 1742, 1663, 1623, 1371, 1236, 1017, 734
cm–1
.
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1H NMR (300 MHz, CDCl3): δ = 2.02 (s, 3 H, CH3CO, R or S), 2.08 (s, 3 H,
CH3CO, R or S), 2.10 (s, 3 H, CH3CO, R or S), 2.14 (s, 3 H, CH3CO, R or S),
3.79 (dd, J = 12.1, 2.0 Hz, 1 H, H-6, R or S), 4.03 (ddd, J = 9.4, 4.7, 2.0 Hz,
1 H, H-5, R or S), 4.11 (dd, J = 12.1, 5.1 Hz, 1 H, H-6′, R or S), 4.28–4.36
(m, 3 H, H-5, H-6 and H-6′, R or S), 5.12 (d, J = 2.8 Hz, 1 H, H-1, R or S),
5.33–5.38 (m, 2 H, H-4, R/S), 5.45 (br s, 1 H, H-1, R or S), 5.86 (ddd, J =
10.1, 2.7, 2.7 Hz, 1 H, H-2, R or S), 5.91–5.96 [m, 3 H (H-2, R or S; H-3,
R/S)], 6.15, 6.17 (2 × s, 2 H, CHO, R/S), 7.32–7.45 (m, 6 H, HAr, R/S), 7.53
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3529–3541

3541
V. N. Melo et al.
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Synthesis
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