Synthesis of 2-Azidomethyl-5-ethynylfuran: A New Bio-Derived Self-Clickable Building Block

Article abstract of DOI:10.1055/s-0037-1610414

2-Azidomethyl-5-ethynylfuran, a new ambivalent compound with both azide and alkyne moieties that can be used as a self-clickable monomer, is synthesized starting directly from renewable biomass. The reactivity of the azide group linked to furfural is tested via the efficient preparation of a broad range of furfural-containing triazoles in good to excellent yields using a 'green' copper(I)-catalyzed azide-alkyne cycloaddition procedure. Access to new bio-based chemicals and oligomeric materials via a click-chemistry approach is also demonstrated using this bio-derived building block.

Full text of DOI:10.1055/s-0037-1610414

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
B. Y. Karlinskii et al.
Paper
Synthesis
Synthesis of 2-Azidomethyl-5-ethynylfuran: A New Bio-Derived
Self-Clickable Building Block
Bogdan Ya. Karlinskii
Leonid V. Romashov
Konstantin I. Galkin
Pavel G. Kislitsyn
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2-9
1
3
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N
N
N
CuAAC
O
N3
HO
n
O
O
Valentine P. Ananikov*
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2-6
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7-
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O
HMF
Plant biomass
Self-clickable building block
suitable for intermolecular
cycloaddition
N. D. Zelinsky Institute of Organic Chemistry of the Russian
Academy of Sciences, Leninsky prospect 47, Moscow, 119991,
Russian Federation
val@ioc.ac.ru
Published as part of the 50 Years SYNTHESIS – Golden
Anniversary Issue
Type 1
Received: 05.10.2018
Native or modified functional groups
Accepted after revision: 26.11.2018
Published online: 08.01.2019
DOI: 10.1055/s-0037-1610414; Art ID: ss-2018-z0676-op
FG[O] - oxygen-containing functional groups
(carbonyl, acyl, amide, ester, etc.), most
easily accessible in biomass processing
procedures
[O]FG
FG[O]
O
~300 examples
License terms:
Type 2
One new functional group
FG - synthetically installed oxygen-free
functional group (alkynyl, aryl, amine,
nitrile, azide, etc.)
Abstract 2-Azidomethyl-5-ethynylfuran, a new ambivalent compound
with both azide and alkyne moieties that can be used as a self-clickable
monomer, is synthesized starting directly from renewable biomass. The
reactivity of the azide group linked to furfural is tested via the efficient
preparation of a broad range of furfural-containing triazoles in good to
excellent yields using a ‘green’ copper(I)-catalyzed azide–alkyne cyc-
loaddition procedure. Access to new bio-based chemicals and oligomer-
ic materials via a click-chemistry approach is also demonstrated using
this bio-derived building block.
Plant biomass
FG
FG[O]
O
~530 examples
O
HO
O
Type 3
HMF
Two new functional groups
FG
FG
O
~70 examples
Key words 5-(hydroxymethyl)furfural, click chemistry, biomass con-
This work
N3
version, triazoles, oligomers
O
Unknown
The production and conversion of bio-derived platform
chemicals and building blocks has received significant at-
tention in order to meet the demands of sustainable devel-
opment and green chemistry concepts.1 5-(Hydroxymeth-
yl)furfural (HMF), produced by catalytic dehydration of
hexose carbohydrates, has been recently nominated as a
‘sleeping giant’2 of sustainable chemistry, possessing nu-
merous applications especially in the production of biofu-
els,3 polymers4 and fine chemicals.5 However, most of the
described HMF derivatives were afforded by various redox
processes and therefore comprise one or two oxygen-con-
taining functional groups (Scheme 1, Types 1 and 2),
whereas literature reports on bio-based furans with two
oxygen-free functional groups (Scheme 1, Type 3) are less
prominent. Furthermore, the vast majority of HMF-based
materials are either polyesters or polyamides.4 Examples of
HMF-based polymers with other types of backbone remain
quite rare.
Scheme 1 Three types of HMF derivatives (according to a literature
search;6 for representative examples see the reviews1a,b
)
The introduction of two oxygen-free functional groups
into bio-derived sustainable building blocks is currently
one of the key research directions. This problem is especial-
ly challenging for the cases of two mutually reactive func-
tional groups, for example, azide and alkyne fragments that
are able to quickly combine into a triazole via a Huisgen di-
polar cycloaddition.7 A catalytic modification of this reac-
tion, the copper(I)-catalyzed azide–alkyne cycloaddition
(CuAAC), has proved to be one of the most important link-
ing reactions for click-chemistry applications.8 It usually
proceeds under mild conditions with high yields and regi-
oselectivity and has numerous advantages for use in mate-
rials science,9 drug development10 and other fields of or-
ganic, bioorganic and medicinal chemistry.11
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

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B. Y. Karlinskii et al.
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Synthesis
Indeed, among a small number of HMF derivatives with
two oxygen-free functional groups there is only one exam-
ple each of the synthesis of alkyne- or azide-containing fu-
ranyls: 2,5-diethynylfuran12 and 2,5-bis(azidomethyl)fu-
ran,13 but there are no examples of combining these moi-
eties in one molecule. More generally, only a few azide14
and alkyne15 derivatives have been synthesized from bio-
mass-derived furans, despite their unquestionable rele-
vance for the easy and rapid ‘click’ synthesis of triazoles,16
which are themselves reported to have antitubercular17 and
anticancer18 activity.
In this work, we report a synthetic route to the new,
‘self-clickable’ building block, 2-azidomethyl-5-ethynylfu-
ran (AMEF) (6). The term ‘self-clickable’ describes an ambiv-
alent reactivity and ability to engage in intermolecular cyc-
loaddition related to the presence of both azide and alkyne
moieties. This duality allows ‘click’ polycondensation19 to
be carried out under mild conditions leading to heterocyclic
furan-triazole oligomers. In addition, a number of new bio-
based triazoles were obtained via a model reaction involv-
ing the precursor of AMEF, 5-(azidomethyl)furfural (AMF)
(3), following classical CuAAC methodology under mild
conditions. To implement the bio-derived strategy, the
available bulk constituents of natural biomass (cellulose
and fructose) were tested as the feedstock for this synthe-
sis.
In the next stage, HMF was converted into 5-(chloro-
methyl)furfural (CMF) (2) using hydrogen chloride in a bi-
phasic system, with the product being obtained in 92%
yield. It should be noted that CMF itself can be discussed as
a platform chemical since it can be obtained directly from
biomass in good yield.21 Subsequent nucleophilic substitu-
tion of the chlorine in CMF with sodium azide under mild
conditions afforded AMF (3) with almost complete conver-
sion.
To probe the reactivity of the azide group linked to a
furfural moiety, AMF was subsequently utilized in a series
of CuAAC reactions with various alkynes. A range of new bi-
heterocyclic compounds 4a–q was synthesized in good to
excellent yields in these experiments (Scheme 3). All reac-
tions were carried out under mild conditions in the pres-
ence of air, using aqueous ethanol as the solvent and with
almost stoichiometric ratios of reagents without any purifi-
cation of products. The use of classic CuAAC methodology is
nicely compatible with a wide range of terminal alkynes in
this cycloaddition reaction. Nevertheless, it is known that
alkynes with internal triple bonds are significantly less re-
active; for example, the reaction of AMF with deca-1,4-
diyne resulted in the formation of only one product 4d
without involving the internal triple bond in the cycloaddi-
tion. In spite of the high practical interest of biomass con-
version and furan-based platform chemicals, this work rep-
resents the first study of the reactivity of HMF-derived
azide 3 in CuAAC reactions and the preparation of new
compounds 4a–q.6
The synthesis of reactive self-clickable AMEF (6) was
performed by two methods. The more efficient approach
was a two-stage process starting with substitution of the
aldehyde fragment in HMF with an acetylenic moiety using
the Bestmann–Ohira reagent (dimethyl 1-diazo-2-oxopro-
pylphosphonate). The formation of 2-hydroxymethyl-5-
ethynylfuran (HMEF) (5) in 97% yield was followed by sub-
stitution of the hydroxy group with an azide moiety from
diphenylphosphoryl azide (DPPA) in the presence of DBU.
The yield after chromatography was 86%; thus utilization of
this methodology resulted in an overall yield of AMEF of
83% from HMF.
Another method for the synthesis of AMEF involves the
introduction of an acetylenic moiety on AMF via alkynyla-
tion of the aldehyde group by using potassium carbonate
and the Bestmann–Ohira reagent. The target product 6 was
isolated by column chromatography on silica gel in a mod-
erate 41% yield (37% overall yield from HMF) and showed
relatively good stability at reduced temperatures (below
–5 °C).
The synthesis of compounds 3 and 6 was carried out us-
ing renewable resources as starting materials (Scheme 2). In
the first stage, we conducted the Lewis or Brønsted acid
catalyzed dehydration of natural carbohydrates (cellulose
or fructose, respectively) into HMF (1), which was isolated
in a pure crystalline form, as described previously.20
N
N
R
O
N
O
4a–q
71–99%
CuAAC
R
HCl
NaN3
99%
O
N3
O
Cl
92%
O
O
3
2
AMF
CMF
Cat.
O
OH
fructose or
cellulose
Bestmann–Ohira
reagent
41%
O
up to
90%
1
HMF
DPPA
OH
N3
O
5
HMEF
O
6
AMEF
86%
97%
Bestmann–Ohira
reagent
CuAAC
up to 91%
To evaluate the synthetic potential of AMEF as a mono-
mer, we conducted a study of its ‘click’ polycondensation
using different Cu-based catalytic systems: aqueous etha-
nol as a green solvent with the classic copper(II) sulfate and
sodium ascorbate couple, being an alternative to polycon-
densation in DMF with copper(I) bromide in the presence
N
N
n
N
O
7
Scheme 2 A proposed synthetic strategy affording new bio-based
building blocks and oligomers via click-chemistry approach
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

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B. Y. Karlinskii et al.
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Synthesis
N
CuSO4•5H2O (5 mol%)
(+)-sodium L-ascorbate (10 mol%)
N
N
R
O
O
N3
1.2
R
+
O
O
EtOH–H2O (50%)
50 °C, 3 h
4a–q
3
N
O
N
N
N
N
N
N
N
N
N
N
N
OH
N
O
O
O
O
O
N
N
O
O
O
O
O
O
4a
93%
4b
89%
4c 98%
4d
96%
4e
77%
NHBoc
OH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
N
O
N
O
O
OH
O
O
O
O
O
N
4ha
4f
95%
N
4g
95%
96%
4i
71%
4j
99%
O
OH
OH
N
N
N
N
N
N
N
N
N
N
O
O
N
N
O
O
O
N
N
O
O
O
O
O
4lb
4k
88%
96%
4m
87%
4n
96%
4o
95%
N
N
N
N
N
N
N
N
N
N
N
N
4pc 72%
4qc 89%
O
O
O
O
O
O
O
O
Scheme 3 Synthesis of triazole derivatives of AMF (isolated yields are shown); a 1.05 equiv of the corresponding alkyne was used; b 1.5 equiv of the
corresponding alkyne was used; c 0.45 equiv of the corresponding alkyne was used
of different ligands (Table 1). The best performance was
shown in the case of the CuBr/PMDETA system (Table 1, en-
try 1).
DSC measurements (see the Supporting Information), as all
of the oligomer samples showed strong exothermic effects
at temperatures above 200 °C. Apparently, this is due to the
presence of relatively energy-rich azide fragments in the
material.
The microstructures of the prepared oligomer samples
were studied by means of scanning electron microscopy
(FE-SEM) (Figure 1). The substances had similar morpholo-
gies of sharp-edged particles whenever DMF was used as
the solvent. Thus, the sample morphologies were almost in-
dependent of the used catalytic system and were tolerant to
variations in the catalyst (Figure 1, A–D). To modify the
morphology, aqueous ethanol was used as the reaction me-
dium, leading to the formation of larger particles with
smooth edges (Figure 1, E and F).
Table 1 Cu-Catalyzed Polymerization of AMEF Using Different Catalyt-
ic Systems
Entry
Catalyst
Solvent
Yield
1
2
3
4
5
CuBr/PMDETA
CuBr/TEEDA
DMF
91%
84%
76%
79%
70%
DMF
CuBr/bipy
DMF
CuBr/phen
DMF
CuSO4/sodium ascorbate
EtOH/H2O
In conclusion, we have, for the first time, synthesized an
ambivalent compound with both azide and alkyne moieties
from renewable sources. The synthesis provides an access
to a new type of biheterocyclic oligomers under mild condi-
tions following classical click-chemistry methodology. The
oligomers were characterized by NMR, IR, DSC and FE-SEM
studies. In addition, a broad range of triazoles with a furfu-
ral moiety was prepared in good to excellent yields in ac-
cordance with green chemistry requirements. The ap-
proach paves the way for the application of Cu-catalyzed
As a result of polycondensation, oligomers were ob-
tained as colored solids (the color depended on the catalytic
system used) that were slightly soluble in dipolar aprotic
solvents such as DMF and DMSO. The number-average mo-
lecular weight of the oligomers was estimated roughly as
4100 g/mol by integration of the terminal azide end-group
signal (4.51 ppm) relative to the signals of the rest of the
1
chain in the H NMR spectra. The oligomers were found to
be thermally transformable. This finding was confirmed by
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

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B. Y. Karlinskii et al.
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Synthesis
also recorded at –60 °C (Bruker Avance 600 NMR spectrometer, 151
MHz), since at room temperature two of the signals were rather broad
and difficult to detect, most likely due to dynamic or relaxation prop-
erties (see the Supporting Information). Electrospray ionization mass
spectrometry (ESI-MS) was performed on a high-resolution time-of-
flight Bruker maXis instrument. The spectra were processed using the
Bruker Data Analysis 4.0 software package. Analysis of sample mor-
phology was carried out using a Hitachi SU8000 field-emission scan-
ning electron microscope. DSC analysis was performed on a Mettler
Toledo DSC823e calorimeter equipped with an FSR 5 thermocouple
and a liquid nitrogen cooling block. The samples were placed in 40 μL
aluminum crucibles with perforated caps. Perforation allowed free at-
mosphere exchange with the oven to obtain results at a constant
pressure. The samples were heated under an argon atmosphere (flow:
70 mL/min). Data processing was performed using the STARe service
program.
5-(Azidomethyl)furfural (AMF) (3)
Sodium azide (4.5 g, 69.2 mmol) was added to a solution of 5-(chloro-
methyl)furfural (5.0 g, 34.6 mmol) in acetonitrile (100 mL). The mix-
ture was stirred for 6 h at room temperature, filtered through Celite,
and the filtrate was evaporated at 30 °C. The residue was dissolved in
diethyl ether and refiltered through Celite to remove inorganic impu-
rities. After evaporation, 5-(azidomethyl)furfural (3) was obtained as
a yellow oil (5.18 g, 99%).
Figure 1 Field-emission scanning electron microscopy (FE-SEM) imag-
es of the synthesized oligomers prepared from AMEF (6) using the cata-
lytic systems listed in Table 1 (entries 1–5): 1 (A), 2 (B), 3 (C), 4 (D) and
5 (E and F); 50 μm scale bars are shown below images A–E and a 100
μm scale bar is shown below image F.
IR (KBr): 3123, 2838, 2101, 1678, 1522, 1402, 1275, 1024, 810 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 4.40 (s, 2 H), 6.54 (d, J = 3.5 Hz, 1 H),
7.21 (d, J = 3.5 Hz, 1 H), 9.62 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 47.1, 111.5, 121.9, 153.1, 155.4, 177.7.
HRMS (ESI): m/z [M + Na]+ calcd for C6H5N3O2Na: 174.0274; found:
174.0279.
systems for the construction of bio-based biheterocyclic
compounds and is expected to provide attractive solutions
for the development of new building blocks and the design
of bio-based organic materials. The direct involvement of
natural biomass as a sustainable source of chemicals is one
of the most promising trends in synthetic chemistry and
more detailed studies on the subject are to be anticipated in
the near future.
Dipolar Cycloaddition of 5-(Azidomethyl)furfural (3) to Alkynes;
General Procedure
5-(Azidomethyl)furfural (3) (200 mg, 1.32 mmol) in an 8 mL glass vial
was dissolved in 50% aqueous ethanol (3 mL) followed by the addition
of copper sulfate pentahydrate (16 mg, 0.07 mmol) and sodium ascor-
bate (26 mg, 0.13 mmol). Next, an appropriate amount of alkyne (typ-
ically 1.58 mmol; 1.38 mmol of N-Boc-propargylamine; 1.98 mmol of
3,3-dimethylbut-1-yne) was added, and the reaction mixture was
stirred at 50 °C for 3 h. For triazoles insoluble in aqueous ethanol (4b,
4e, 4j), the reaction mixture was diluted with water (10 mL) and the
precipitate was filtered, washed with water and dried under vacuum.
Drying was completed in a desiccator over phosphorus pentoxide. For
triazoles soluble in aqueous ethanol (4a,c,d,f–i,k–o), the solvent was
evaporated under vacuum, the residue dissolved in chloroform and
filtered through Celite. Subsequent evaporation under vacuum at
50 °C yielded the pure triazoles.
Caution! Sodium azide is highly toxic and should be handled with ex-
treme care. All reagents from commercial sources were checked by
NMR before use or were purified by standard methods.22 HMF (1),20
CMF (2),5e N-Boc-propargylamine,23 HMEF (5),12 diphenylphosphoryl
azide (DPPA)24 and dimethyl 1-diazo-2-oxopropylphosphonate (Best-
mann–Ohira reagent)25 were prepared according to the published
procedures. All reactions were performed in oven-dried (120 °C)
glassware. Chromatographic separations were performed on silica gel
(Kieselgel, 230–400 mesh, Merck Schuchardt) with analytical grade
solvents. Analytical TLC was performed on Merck silica gel plates with
QF-254 indicator. Visualization was accomplished with UV light (254
nm). Melting points were determined using a 1101D Mel-Temp appa-
ratus and are uncorrected. IR spectra were recorded on a Bruker Al-
pha-T spectrophotometer. NMR spectra were recorded using a Bruker
Fourier 300 HD spectrometer at frequencies of 300.1 MHz (1H) and
75.5 MHz (13C) with the residual solvent peak as an internal standard.
Unless otherwise noted, NMR spectra were recorded at room tem-
perature. The spectra were processed using MestReNova software.
The 13C NMR spectra of compounds 4a, 4c, 4f, 4i, 4k, 4m and 4n were
5-{[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]methyl}furfu-
ral (4a)
Yield: 288 mg (93%); yellowish-brown crystals; mp 85–88 °C.
IR (KBr): 3322, 3139, 1668, 1527, 1403, 1019, 977, 792 cm–1
1H NMR (300 MHz, CD2Cl2): δ = 1.58 (s, 6 H), 5.62 (s, 2 H), 6.63 (d, J =
3.5 Hz, 1 H), 7.22 (d, J = 3.5 Hz, 1 H), 7.68 (br s, 1 H), 9.58 (s, 1 H).
13C NMR (151 MHz, CDCl3, –60 °C): δ = 29.9, 46.3, 67.8, 112.9, 120.0,
125.6, 152.1, 153.6, 156.1, 177.8.
HRMS (ESI): m/z [M + Na]+ calcd for C11H13N3O3Na: 258.0849; found:
258.0845.
.
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Synthesis
5-[(4-Phenyl-1H-1,2,3-triazol-1-yl)methyl]furfural (4b)
5-{[4-(4-Hydroxybutyl)-1H-1,2,3-triazol-1-yl]methyl}furfural (4g)
Yield: 298 mg (89%); yellow crystals; mp 122–125 °C.
Yield: 314 mg (95%); yellow crystals; mp 60–63 °C.
IR (KBr): 3116, 1676, 1525, 1195, 1027, 765, 693 cm–1
.
IR (KBr): 3344, 3118, 2934, 1681, 1525, 1264, 1027, 774 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.68 (s, 2 H), 6.63 (d, J = 3.6 Hz, 1 H),
7.23 (d, J = 3.6 Hz, 1 H), 7.32–7.37 (m, 1 H), 7.41–7.46 (m, 2 H), 7.81–
7.84 (m, 2 H), 7.90 (s, 1 H), 9.65 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 46.9, 112.5, 120.0, 122.1, 126.0, 128.6,
129.1, 130.2, 148.7, 153.3, 153.5, 177.7.
1H NMR (300 MHz, CDCl3): δ = 1.57–1.66 (m, 2 H), 1.70–1.80 (m, 2 H),
1.95 (br s, 1 H), 2.74 (t, J = 7.4 Hz, 2 H), 3.65 (t, J = 6.3 Hz, 2 H), 5.58 (s,
2 H), 6.55 (d, J = 3.6 Hz, 1 H), 7.20 (d, J = 3.6 Hz, 1 H), 7.44 (s, 1 H), 9.60
(s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 25.4, 25.6, 32.2, 46.7, 62.4, 112.3, 121.2,
122.2, 148.9, 153.1, 153.8, 177.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H16N3O3: 250.1186; found:
HRMS (ESI): m/z [M + H]+ calcd for C14H12N3O2: 254.0924; found:
254.0930.
250.1186.
5-[(4-Pentyl-1H-1,2,3-triazol-1-yl)methyl]furfural (4c)
5-{[4-(N-Boc-aminomethyl)-1H-1,2,3-triazol-1-yl]methyl}furfu-
ral (4h)
Yield: 320 mg (98%); yellowish-green crystals; mp 63–66 °C.
IR (KBr): 3065, 2927, 1674, 1532, 1266, 1018, 977, 799 cm–1
.
Yield: 388 mg (96%); yellow crystals; mp 106–110 °C.
1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H), 1.32–1.34 (m, 4
H), 1.67–1.71 (m, 2 H), 2.70 (br s, 2 H), 5.60 (s, 2 H), 6.56 (d, J = 3.5 Hz,
1 H), 7.20 (d, J = 3.5 Hz, 1 H), 7.49 (br s, 1 H), 9.62 (s, 1 H).
13C NMR (151 MHz, CDCl3, –60 °C): δ = 14.3, 22.5, 25.5, 29.1, 31.4,
46.3, 112.5, 121.3, 125.5, 149.2, 152.0, 153.9, 177.6.
IR (KBr): 3403, 1683, 1512, 1272, 1169, 793 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.41 (s, 9 H), 4.38 (d, J = 5.9 Hz, 2 H),
5.15 (br s, 1 H), 5.59 (s, 2 H), 6.56 (d, J = 3.2 Hz, 1 H), 7.20 (d, J = 3.4 Hz,
1 H), 7.63 (s, 1 H), 9.62 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 28.5, 36.2, 46.8, 79.9, 112.5, 121.8,
122.3, 146.5, 153.3, 153.4, 155.9, 177.7.
HRMS (ESI): m/z [M + H]+ calcd for C13H18N3O2: 248.1394; found:
248.1392.
HRMS (ESI): m/z [M + H]+ calcd for C14H19N4O4: 307.1401; found:
307.1401.
5-{[4-(Oct-2-yn-1-yl)-1H-1,2,3-triazol-1-yl]methyl}furfural (4d)
Yield: 362 mg (96%); brown oil.
IR (KBr): 3128, 2930, 1681, 1523, 1403, 1024, 790 cm–1
1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.29–1.36 (m, 4
H), 1.45–1.54 (m, 2 H), 2.14–2.20 (m, 2 H), 3.67 (s, 2 H), 5.60 (s, 2 H),
6.58 (d, J = 3.5 Hz, 1 H), 7.20 (d, J = 3.5 Hz, 1 H), 7.60 (s, 1 H), 9.62 (s, 1
H).
5-[(4-Hydroxymethyl-1H-1,2,3-triazol-1-yl)methyl]furfural (4i)
.
Yield: 195 mg (71%); yellow crystals; mp 75–79 °C.
IR (KBr): 3370, 1662, 1528, 1267, 1133, 1013, 795 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.59 (br s, 1 H), 4.79 (br s, 2 H), 5.61 (s,
2 H), 6.59 (d, J = 3.5 Hz, 1 H), 7.20 (d, J = 3.5 Hz, 1 H), 7.77 (br s, 1 H),
9.60 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 14.1, 16.8, 18.9, 22.3, 28.6, 31.2, 46.8,
75.6, 82.7, 112.4, 122.0, 146.1, 153.2, 153.6, 177.7.
13C NMR (151 MHz, CDCl3, –60 °C): δ = 46.5, 54.9, 112.9, 122.9, 125.5,
148.2, 152.1, 153.4, 177.7.
HRMS (ESI): m/z [M + H]+ calcd for C9H10N3O3: 208.0717; found:
HRMS (ESI): m/z [M + H]+ calcd for C16H20N3O2: 286.1550; found:
286.1551.
208.0715.
5-[(4-Methoxycarbonyl-1H-1,2,3-triazol-1-yl)methyl]furfural (4e)
5-{[4-(Quinolin-3-yl)-1H-1,2,3-triazol-1-yl]methyl}furfural (4j)
Yield: 240 mg (77%); red crystals; mp 125–127 °C.
Yield: 398 mg (99%); orange crystals; mp 179–183 °C.
IR (KBr): 3424, 3130, 1680, 1497, 1030, 827, 786, 759 cm–1
IR (KBr): 3123, 2838, 1727, 1674, 1548, 1333, 1241, 1017, 813 cm–1
1H NMR (300 MHz, DMSO-d6): δ = 3.84 (s, 3 H), 5.88 (s, 2 H), 6.83 (d,
J = 3.6 Hz, 1 H), 7.53 (d, J = 3.6 Hz, 1 H), 8.88 (s, 1 H), 9.57 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 46.1, 51.8, 112.6, 123.9, 129.5,
138.8, 152.5, 153.9, 160.5, 178.4.
.
.
1H NMR (300 MHz, DMSO-d6): δ = 5.94 (s, 2 H), 6.90 (d, J = 3.5 Hz, 1
H), 7.57 (d, J = 3.5 Hz, 1 H), 7.61–7.66 (m, 1 H), 7.77 (t, J = 7.3 Hz, 1 H),
8.06 (d, J = 8.0 Hz, 2 H), 8.82 (s, 1 H), 8.91 (s, 1 H), 9.44 (br s, 1 H), 9.59
(s, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 46.2, 112.7, 122.7, 123.7, 124.0,
127.2, 127.6, 128.3, 128.8, 129.7, 131.1, 144.2, 147.1, 148.2, 152.6,
154.3, 178.5.
HRMS (ESI): m/z [M + H]+ calcd for C10H10N3O4: 236.0666; found:
236.0667.
5-{[4-(3-Cyanopropyl)-1H-1,2,3-triazol-1-yl]methyl}furfural (4f)
HRMS (ESI): m/z [M + H]+ calcd for C17H13N4O2: 305.1033; found:
305.1032.
Yield: 306 mg (95%); brown crystals; mp 70–74 °C.
IR (KBr): 3113, 2243, 1675, 1530, 1270, 972, 795 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.06 (br s, 2 H), 2.40–2.44 (m, 2 H),
2.86 (br s, 2 H), 5.61 (s, 2 H), 6.58 (d, J = 3.5 Hz, 1 H), 7.20 (d, J = 3.5 Hz,
1 H), 7.61 (br s, 1 H), 9.59 (s, 1 H).
13C NMR (151 MHz, CDCl3, –60 °C): δ = 16.6, 24.0, 24.5, 46.4, 112.7,
119.9, 122.0, 125.5, 146.2, 152.1, 153.5, 177.7.
5-[(4-Methoxymethyl-1H-1,2,3-triazol-1-yl)methyl]furfural (4k)
Yield: 257 mg (88%); brown oil.
IR (KBr): 3126, 2932, 1681, 1524, 1402, 1274, 1195, 1094, 793 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.40 (s, 3 H), 4.54 (s, 2 H), 5.61 (s, 2 H),
6.56 (d, J = 3.5 Hz, 1 H), 7.19 (d, J = 3.5 Hz, 1 H), 7.78 (br s, 1 H), 9.60 (s,
1 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H13N4O2: 245.1033; found:
245.1037.
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13C NMR (151 MHz, CDCl3, –60 °C): δ = 29.9, 46.3, 67.8, 112.9, 120.0,
125.6, 152.1, 153.6, 156.1, 177.8.
HRMS (ESI): m/z [M + H]+ calcd for C10H12N3O3: 222.0873; found:
222.0876.
mmol) were added. Next, the corresponding alkyne (0.60 mmol) was
added and the reaction mixture was stirred at 50 °C for 3 h. The mix-
ture was diluted with water (10 mL) and the precipitate was filtered,
washed with water and dried under vacuum. Drying was completed
in a desiccator over phosphorus pentoxide.
5-{[4-(tert-Butyl)-1H-1,2,3-triazol-1-yl]methyl}furfural (4l)
5,5′-{[Propane-1,3-diylbis(1H-1,2,3-triazole-4,1-diyl)]bis(methy-
lene)}bis(furfural) (4p)
Yield: 298 mg (96%); yellow crystals; mp 98–101 °C.
IR (KBr): 3123, 2966, 1674, 1526, 1221, 1050, 763 cm–1
.
Yield: 171 mg (72%); white crystals; mp 141–144 °C.
1H NMR (300 MHz, CDCl3): δ = 1.33 (s, 9 H), 5.57 (s, 2 H), 6.55 (d, J =
3.5 Hz, 1 H), 7.20 (d, J = 3.5 Hz, 1 H), 7.36 (s, 1 H), 9.62 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 30.4, 30.9, 46.6, 112.3, 118.9, 122.2,
153.1, 154.0, 158.6, 177.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H16N3O2: 234.1237; found:
IR (KBr): 3063, 1673, 1532, 1221, 1018, 797 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 1.91 (quin, J = 7.7 Hz, 2 H), 2.66 (t,
J = 7.6 Hz, 4 H), 5.75 (s, 4 H), 6.76 (d, J = 3.6 Hz, 2 H), 7.51 (d, J = 3.6 Hz,
2 H), 7.95 (s, 2 H), 9.56 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 24.4, 28.6, 45.7, 112.2, 122.4, 124.0,
146.9, 152.4, 154.9, 178.4.
234.1235.
HRMS (ESI): m/z [M + H]+ calcd for C19H19N6O4: 395.1462; found:
395.1461.
5-[(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]furfural (4m)
Yield: 250 mg (87%); yellow crystals; mp 99–102 °C.
IR (KBr): 3088, 1673, 1525, 1016, 976, 765 cm–1
.
5,5′-{[1,3-Phenylenebis(1H-1,2,3-triazole-4,1-diyl)]bis(methy-
1H NMR (300 MHz, CDCl3): δ = 0.83–0.94 (m, 4 H), 1.93 (br s, 1 H),
5.55 (s, 2 H), 6.54 (d, J = 3.5 Hz, 1 H), 7.19 (d, J = 3.5 Hz, 1 H), 7.45 (br s,
1 H), 9.60 (s, 1 H).
13C NMR (151 MHz, CDCl3, –60 °C): δ = 6.7, 8.3, 46.3, 112.5, 120.3,
125.6, 151.0, 152.0, 153.9, 177.7.
lene)}bis(furfural) (4q)
Yield: 229 mg (89%); pale yellow crystals; mp 136–139 °C.
IR (KBr): 3449, 3122, 1685, 1655, 1524, 1193, 1025, 787 cm–1
1H NMR (300 MHz, DMSO-d6): δ = 5.88 (s, 4 H), 6.86 (d, J = 3.5 Hz, 2
H), 7.50–7.56 (m, 3 H), 7.84 (dd, J = 7.7, 1.2 Hz, 2 H), 8.37 (s, 1 H), 8.73
(s, 2 H), 9.58 (s, 2 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C11H12N3O2: 218.0924; found:
218.0927.
13C NMR (75 MHz, DMSO-d6): δ = 46.1, 112.5, 121.9, 122.0, 123.9,
124.8, 129.6, 131.0, 146.4, 152.5, 154.4, 178.4.
HRMS (ESI): m/z [M + H]+ calcd for C22H17N6O4: 429.1306; found:
429.1303.
5-{[4-(2-Hydroxy-4-methylpentan-2-yl)-1H-1,2,3-triazol-1-
yl]methyl}furfural (4n)
Yield: 352 mg (96%); brown oil.
IR (KBr): 3409, 2956, 1681, 1523, 1195, 1049, 789 cm–1
.
2-Azidomethyl-5-ethynylfuran (AMEF) (6)
1H NMR (300 MHz, CDCl3): δ = 0.80 (d, J = 5.5 Hz, 3 H), 0.85 (d, J = 5.5
Hz, 3 H), 1.58 (s, 3 H), 1.68–1.80 (m, 3 H), 2.61 (br s, 1 H), 5.60 (s, 2 H),
6.55 (d, J = 1.6 Hz, 1 H), 7.20 (d, J = 2.1 Hz, 1 H), 7.60 (br s, 1 H), 9.60 (s,
1 H).
13C NMR (151 MHz, CDCl3, –60 °C): δ = 24.28, 24.29, 24.34, 28.4, 46.4,
50.8, 71.1, 112.7, 120.4, 125.6, 152.1, 153.7, 155.9, 177.7.
From 2-hydroxymethyl-5-ethynylfuran (HMEF) (5): Diphenylphos-
phoryl azide (0.84 g, 3.0 mmol) was added under an argon atmo-
sphere to an ice-cold solution of 2-hydroxymethyl-5-ethynylfuran (5)
(0.25 g, 2.0 mmol) in acetonitrile (10 mL), followed by the addition of
DBU (0.45 mL, 3.0 mmol). The reaction mixture was stirred for 10 h
and concentrated under vacuum. The residue was diluted with water
(10 mL) and dichloromethane (10 mL) and acidified with dilute hy-
drochloric acid. The aqueous layer was separated and extracted with
dichloromethane (2 to 10 mL). The organic fractions were combined,
dried over anhydrous magnesium sulfate and evaporated at 30 °C. The
residue was purified by column chromatography on silica gel to afford
6 as a yellow liquid (0.26 g, 86%). Rf = 0.45 (hexanes/EtOAc, 4:1).
HRMS (ESI): m/z [M + H]+ calcd for C14H20N3O3: 278.1499; found:
278.1501.
5-{[4-(2-Hydroxy-3,3-dimethylbutan-2-yl)-1H-1,2,3-triazol-1-
yl]methyl}furfural (4o)
Yield: 349 mg (95%); brown crystals; mp 96–99 °C.
IR (KBr): 3426, 2965, 1681, 1523, 1376, 1210, 1071, 774 cm–1
1H NMR (300 MHz, DMSO-d6): δ = 0.85 (s, 9 H), 1.44 (s, 3 H), 4.88 (br
s, 1 H), 5.76 (s, 2 H), 6.74 (d, J = 3.5 Hz, 1 H), 7.52 (d, J = 3.5 Hz, 1 H),
7.89 (s, 1 H), 9.56 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 23.6, 25.3, 37.3, 45.6, 74.0, 112.1,
123.0, 124.1, 152.3, 154.4, 155.0, 178.3.
HRMS (ESI): m/z [M + H]+ calcd for C14H20N3O3: 278.1499; found:
278.1495.
From 5-(azidomethyl)furfural (AMF) (3): Potassium carbonate (1.8 g,
13.2 mmol) was placed in a 100 mL Schlenk flask. A vacuum was ap-
plied and then the flask was repeatedly flushed with argon. A solution
of 5-(azidomethyl)furfural (3) (1.0 g, 6.6 mmol) in absolute methanol
(50 mL) was added, the mixture was stirred under an argon atmo-
sphere for 10 min at room temperature and then Bestmann–Ohira re-
agent (1.2 mL, 7.9 mmol) was added dropwise. The mixture was
stirred overnight at room temperature, diluted with dichloromethane
(100 mL), washed with water (100 mL) and brine (2 × 50 mL), and
dried over anhydrous magnesium sulfate. The solvent was removed at
30 °C under reduced pressure and the residue was purified by column
chromatography on silica gel to afford 6 as a yellow liquid (0.40 g,
41%). Rf = 0.45 (hexanes/EtOAc, 4:1).
.
Dipolar Cycloaddition of 5-(Azidomethyl)furfural (3) to Com-
pounds with Two Terminal Alkyne Moieties
IR (KBr): 3290, 3127, 2098, 1404, 1203, 1019, 798 cm–1
.
5-(Azidomethyl)furfural (3) (200 mg, 1.32 mmol) in an 8 mL glass vial
was dissolved in 50% aqueous ethanol (3 mL) and then copper sulfate
pentahydrate (16 mg, 0.07 mmol) and sodium ascorbate (26 mg, 0.13
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

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B. Y. Karlinskii et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 3.41 (s, 1 H), 4.28 (s, 2 H), 6.34 (d, J =
3.4 Hz, 1 H), 6.62 (d, J = 3.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 47.1, 73.7, 82.5, 110.4, 117.1, 137.0,
Palkovits, R. Energy Environ. Sci. 2014, 7, 2803. (g) Besson, M.;
Gallezot, P.; Pinel, C. Chem. Rev. 2013, 114, 1827. (h) Yu, I. K. M.;
Tsang, D. C. W. Bioresour. Technol. 2017, 238, 716.
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Nature 2007, 447, 982. (b) Saha, B.; Bohn, C. M.; Abu-Omar, M.
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HRMS (ESI): m/z [M + H]+ calcd for C7H6N3O: 148.0505; found:
148.0511.
Synthesis of Oligomers from 2-Azidomethyl-5-ethynylfuran (6)
With dimethylformamide as the solvent: Copper(I) bromide (7.2 mg,
0.05 mmol) in an 8 mL glass vial was dissolved in DMF (2 mL) under
an argon atmosphere. The corresponding ligand (0.10 mmol) was
added and the mixture was stirred for 5 min. 2-Azidomethyl-5-
ethynylfuran (6) (74.0 mg, 0.50 mmol) was added and the mixture
was stirred overnight at room temperature. The oligomer was precip-
itated by addition of methanol (7 mL), filtered, washed with diethyl
ether and dried under vacuum. The yield ranged from 76–91% de-
pending on the ligand used.
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With aqueous ethanol as the solvent: Catalytic amounts of copper sul-
fate pentahydrate (20.4 mg, 0.08 mmol) and sodium ascorbate (20.2
mg, 0.10 mmol) were added to a solution of 2-azidomethyl-5-
ethynylfuran (6) (100.0 mg, 0.68 mmol) in 50% aqueous ethanol (10
mL) and the mixture was stirred overnight. The precipitate that
formed was filtered, washed with 50% aqueous ethanol and ethyl ace-
tate and then dried in a desiccator over phosphorus pentoxide. The
product weight was 70.3 mg (70%).
IR (KBr): 3424, 3144, 1655, 1449, 1343, 1229, 1047, 769 cm–1
.
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1H NMR (300 MHz, DMSO-d6): δ = 5.68–5.75 (m, 2 H), 6.67–6.71 (m, 1
H), 6.76–6.79 (m, 1 H), 8.37–8.44 (m, 1 H).
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Akmalov, T.; Nefedov, S.; Osipov, S.; Nechaev, M.; Asachenko, A.
Eur. J. Org. Chem. 2018, in press; DOI: 10.1002/ejoc.201801538.
(12) Romashov, L. V.; Ananikov, V. P. Chem. Asian J. 2017, 12, 2652.
(13) Dunbabin, A.; Subrizi, F.; Ward, J. M.; Sheppard, T. D.; Hailes, H.
C. Green Chem. 2017, 19, 397.
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Jasheway, K. R.; Wiget, P. A.; Kamat, I.; Anslyn, E. V.; Robertus, J.
D. ACS Med. Chem. Lett. 2012, 3, 588. (b) Goswami, P. P.; Suding,
V. P.; Carlson, A. S.; Topczewski, J. J. Eur. J. Org. Chem. 2016,
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(d) Kazancioglu, E. A.; Kazancioglu, M. Z.; Fistikci, M.; Secen, H.;
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R.; Rashatasakhon, P.; Rose, M. J. Org. Chem. 2003, 68, 2609.
(f) Fabbro, C.; Armani, S.; Carloni, L.-E.; De Leo, F.; Wouters, J.;
Bonifazi, D. Eur. J. Org. Chem. 2014, 5487. (g) Yakushijin, K.;
Suzuki, R.; Kawaguchi, N.; Tsuboi, Y.; Furukawa, H. Chem.
Pharm. Bull. 1986, 34, 2049. (h) Mascal, M.; Dutta, S. Green
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Funding Information
This study was supported by a Russian Science Foundation 17-13-
01176 grant.
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Acknowledgment
We thank Dr. Alexey S. Kashin for FE-SEM characterization, Andrey M.
Tsedilin and Ekaterina A. Denisova for ESI-MS spectra, Artem N.
Fakhrutdinov for low-temperature NMR studies and Irina A. Borisova
for IR services.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610414.
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References
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H