Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis

Article abstract of DOI:10.1016/j.tet.2020.131327

A rapid access to useful 3-azidomethylfurans is developed via Ag(I)-catalyzed cascade annulation/azidation of 2-(1-alkynyl)-2-alken-1-ones. The salient features of the protocol include mild reaction conditions, high efficiency, broad substrate scope, and

Full text of DOI:10.1016/j.tet.2020.131327

Tetrahedron xxx (xxxx) xxx
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Tetrahedron
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Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-
ones enabled by silver catalysis
,
b
,
,
,
, **
Lei-Lei Qian a 1, Ruxia Yi a 1, Xiang-Ting Min a b, Yan-Cheng Hu a, Boshun Wan a
,
Qing-An Chen a
,
*
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
b University of Chinese Academy of Sciences, Beijing, 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid access to useful 3-azidomethylfurans is developed via Ag(I)-catalyzed cascade annulation/azi-
dation of 2-(1-alkynyl)-2-alken-1-ones. The salient features of the protocol include mild reaction con-
ditions, high efficiency, broad substrate scope, and easy scale-up. The formed azide group on the
products could easily undergo further elaborations such as click cycloaddition and reduction.
© 2020 Elsevier Ltd. All rights reserved.
Received 20 April 2020
Received in revised form
4 June 2020
Accepted 6 June 2020
Available online xxx
Keywords:
3-Azidomethylfurans
2-(1-Alkynyl)-2-alken-1-ones
Silver catalysis
Cyclization
Click chemistry
1. Introduction
multi-step synthesis. Therefore, developing an efficient catalytic
protocol that features the construction of the furan ring and the
The furan derivatives are not only core structures in many nat-
ural products, but also important building blocks in organic syn-
thesis [1e11]. Among them, 3-azidomethylfurans, featuring a
combination of azide group and furan skeleton, are of particular
interests [12e14]. Because the azide group can easily undergo
diverse transformations that rapidly elaborate other complex
furan-based heterocycles. For example, they are key intermediates
in the total synthesis of naturally occurring alkaloid stemocurtisine
[15], and also serve as precursors to prepare some bioactive mol-
introduction of azide group in one step, would be highly appealing
yet remains rare [26e29].
In recent years, the annulation of 2-(1-alkynyl)-2-alkenyl-1-
ones has emerged as a versatile paradigm for the rapid assembly
of furan skeletons [30e43]. Nevertheless, one-step synthesis of 3-
azidomethylfurans from 2-(1-alkynyl)-2-alkenyl-1-ones still re-
mains underexploited. In this context, we envisaged that
commercially available TMSN3 possibly serves as a nucleophile to
incorporate with the annulation of 2-(1-alkynyl)-2-alkenyl-1-ones,
resulting in the formation of 3-azidomethylfurans (Scheme 2, c).
Herein, we successfully realized this goal via silver catalysis.
ecules such as a-furanoltriazole [16e18] and furan-based G-aua-
druplex ligands [19e21] (Scheme 1). The known methods towards
the synthesis of 3-azidomethylfurans generally rely on the azida-
tion of pre-synthesized functionalized furan substrates, for
example, nucleophilic substitution of 3-halidemethyl furans and
Lewis acid promoted ring-opening of 3-oxiranefurans (Scheme 2, a,
b) [22e25]. However, such furan precursors also require additional
2. Results and discussion
Our investigation commenced with optimization of the reaction
conditions by using the easily prepared reactant (E)-3-benzylidene-
5-phenylpent-4-yn-2-one (1a) as the model substrate. When
AgSbF6 (10 mol%) was employed as the catalyst, the reaction of 1a
with TMSN3 (1.5 equiv) could take place in DCE at 80 ꢀC, affording
the desired product 3-(azidomethyl)-2-methyl-5-phenylfuran 2a in
29% yield (Table 1, entry 1). The structure of 2a was confirmed by 1H
and 13C NMR and HRMS. The addition of H2O and HOAc as the
* Corresponding author.
** Corresponding author.
E-mail addresses: bswan@dicp.ac.cn (B. Wan), qachen@dicp.ac.cn (Q.-A. Chen).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tet.2020.131327
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: L.-L. Qian et al., Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131327

2
L.-L. Qian et al. / Tetrahedron xxx (xxxx) xxx
Table 1
Optimization of the reaction conditions.
Entry
Catalyst
Temperature (oC)
Solvent
Yield (%)a
1b
2b,c
3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOTf
AgNTf2
AgOAc
AgF
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
40
25
40
40
DCE
DCE
DCE
DCE
THF
DME
MeCN
toluene
MeOH
AcOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
29
48
54
0
35
0
42
86
18
55
68
0
4b,d
5
Scheme 1. Application of 3-azidomethylfuran.
6
7
8
9
10
11
12
13
14
15
16
17
18e
19g
0
0
93
99
90
98f
65
Reaction conditions: 1a (0.20 mmol), TMSN3 (0.30 mmol), catalyst (0.02 mmol),
a
HOAc (0.20 mmol), solvent (2.0 mL), T oC, Ar, 10 h Determined by 1H NMR with
1,3,5-trimethoxybenzene as an internal standard. b No HOAc. c H2O (2 eq.). d TfOH (1
eq.). e AgSbF6 (0.01 mmol). f Isolated yield in 0.50 mmol scale. g air.
substituent, cyclohexyl for instance, was also amenable to the
transformation, but gave a relatively low yield (2p). In the case of 2-
thienyl derived substrate, the annulation failed under standard
conditions, which was possibly ascribed to the strong coordination
between the sulfur atom and the silver catalyst. However, using
Pd(OAc)2 as the catalyst, this expected reaction proceeded
smoothly to deliver the product 2o in 78% yield.
Scheme 2. Approaches for the synthesis of 3-(azidomethyl)furan.
additive led an significant improvement on yields (entries 2e3).
However, no desired product was observed in the presence of
stronger acid TfOH (entry 4). On the basis of this encouraging result,
we then examined various reaction parameters such as solvents,
silver catalysts, and temperatures. The yield of 2a increased to 86%
using toluene as the solvent (entry 8). AgOTf gave an inferior result,
while other silver salts including AgNTf2, AgOAc, and AgF were
ineffective for this transformation (entries 11e14). Moreover, a
nearly quantitative yield was obtained when lowering temperature
to 40 ꢀC (entries 15e17). A small decrease of the catalyst loading
had minimal influence on the efficiency (entry 18). This reaction
could also be carried out under air with a decreased yield (entry
19). Hence the optimized reaction conditions were determined as:
1a (0.2 mmol), TMSN3 (0.3 mmol), AgSbF6 (0.01 mmol), HOAc
(0.2 mmol), toluene (2.0 mL), at 40 ꢀC under argon atmosphere.
With the optimal reaction conditions established, we directed
our efforts to explore the substrate scope of the reaction. The re-
sults are summarized in Schemes 3 and 4. The substituents (R1) on
the alkyne terminus were first investigated. A broad range of aryl
groups in R1 were well compatible with the protocol, affording 3-
(azidomethyl)furans 2be2m in 73e99% yields. The structure of 2d
was unambiguously assigned by a X-ray diffraction analysis. The
electronic properties of the substituents on phenyl ring exerted no
significant impact on the reaction outcome. In comparison, steri-
cally hindered 2-Cl and 2-F substituted substrates could possibly
impede the ring-closure step, thus leading to the corresponding
products (2b, 2e) in slightly decreased yields. The introduce of 1-
Naphthyl in R1 likely hampered the cyclization step, thus deliv-
ering the target product 2n in a moderate yield. The alkyl
Subsequently, the scope of alkene and ketone terminus were
examined (Scheme 4). The annulation of 1v bearing electron-
withdrawing group on the phenyl ring of alkene terminus R2 fur-
nished 3-azidomethylfuran 2v in 73% yield. A variety of aryl groups
in ketone terminus R3 were suitable with the process as well, giving
the desired products in moderate to good yields (2qe2u, 54%e
92%). Remarkably, subjecting a cyclic substrate 1w to the standard
conditions also led to the formation of product 2w in 82% yield [44].
To illustrate the practicability of this approach, a gram-scale
experiment was performed (Scheme 5). The annulation of 2-(1-
alkynyl)-2-alken-1-one 1a with TMSN3 could be easily scaled up
to 5.0 mmol without significant loss of the yield. Given the wide
application of alkyl azides in organic synthesis, the synthetic
elaborations of 2a were further studied (Scheme 5). Cu-catalyzed
click reaction of 2a with phenylacetylene 3a took place efficiently,
affording triazole 4a in 94% yield. The reduction of azide with
LiAlH4 formed the corresponding amine 5a in a high yield.
On the basis of the previous reports [45,46], a plausible mech-
anism was proposed by using the reaction of (E)-3-benzylidene-5-
phenylpent-4-yn-2-one (1a) as an example (Scheme 6). An initial
coordination between the alkynyl moiety of 1a and AgSbF6 induces
an intramolecular cyclization of the carbonyl group to afford car-
bocation B. Then nucleophilic addition of TMSN3 to B gives inter-
mediate C, followed by the protonation to furnish the product 2a
with the regeneration of silver catalyst.
Please cite this article as: L.-L. Qian et al., Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis,
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L.-L. Qian et al. / Tetrahedron xxx (xxxx) xxx
3
Scheme 5. Gram-scale experiment and further derivatization.
Scheme 3. Substrate scope of the alkyne terminus.
Scheme 6. Proposed reaction mechanism.
as click cycloaddition and reduction reaction, would enable our
work to find potential applications in the construction of other
complex furan-based heterocycles.
4. Experimental section
4.1. General
Commercially available reagents were used without further
purification. Solvents were treated prior to use according to the
standard methods. All reactions were carried out under an atmo-
sphere of argon using standard Schlenk techniques or in an argon-
filled glove-box unless otherwise noted. Column chromatography
was carried out on silica gel (300e400 mesh) using a forced flow of
eluent at 0.3e0.5 bar pressure. For TLC, silica gel GF254 was used
and visualized by fluorescence quenching under UV light. NMR
Spectra were recorded on a Bruker 400 MHz NMR spectrometer in
the solvents indicated. The chemical shifts for 1H NMR were
recorded in ppm downfield using the central peak of CDCl3
(7.26 ppm) as the internal standard. The chemical shifts for 13C
NMR were recorded in ppm downfield using the central peak of
CDCl3 (77.16 ppm) as the internal standard. Coupling constants (J)
are reported in Hz and refer to apparent peak multiplications.
Although we have experienced no hazards during the course of
this work, but all reactions with azides should be conducted behind
a blast shield in a fume hood with care. Personal protective
equipment must be worn, including a lab coat, safety glasses, and
Scheme 4. Substrate scope of the alkene and ketone terminus.
3. Conclusion
In summary, we have developed
a
rapid access to 3-
azidomethylfurans via Ag(I)-catalyzed cascade annulation/azida-
tion of 2-(1-alkynyl)-2-alken-1-ones. This methodology features
high efficiency, broad substrate scope, and mild reaction condi-
tions, and its practicability is also highlighted by a gram-scale
experiment. The facile synthetic elaborations of azide group, such
Please cite this article as: L.-L. Qian et al., Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis,
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4
L.-L. Qian et al. / Tetrahedron xxx (xxxx) xxx
gloves with adequate chemical resistance. Keep the hood clear of
any unnecessary chemicals and equipment.
toluene (5.0 mL). The mixture was stirred at 40 ꢀC until the sub-
strate 1 was consumed. The solvent was evaporated and the crude
product was directly purified by flash column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate) to give the desired
product 2.
Organic azides are potentially explosive substances that can
decompose with introduction of external energy (heat, light,
pressure, etc). When affording new organic azides, we should keep
in mind that the number of nitrogen atoms less than one third of
the sum of number of carbon atoms and oxygen atoms (NC þ NO)/
NN ꢁ 3.
4.3.1. 3-(Azido(phenyl)methyl)-2-methyl-5-phenylfuran (2a)
Yellow solid; 141.5 mg; 98% yield; mp 66e67 ꢀC; 1H NMR
The products 3-azidomethylfurans are very stable and can be
stored at room temperature in air. Commercially available trime-
thylsilyl azide (TMSN3) must be sealed and stored in refrigerator.
Use of TMSN3 should be performed in a fume hood since it is a
flammable liquid with toxic properties with route of inhalation.
Organic azide waste should be placed in a separate, explicitly-
labeled container designated solely for azide waste.
(400 MHz, CDCl3)
7.26e7.22 (m, 1H), 6.49 (s, 1H), 5.66 (s, 1H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) 152.3, 149.1, 139.3, 130.6, 128.8, 128.7, 128.1,
d
7.61 (d, J ¼ 8.0 Hz, 2H), 7.40e7.32 (m, 7H),
d
127.4, 127.0, 123.6, 120.4, 105.3, 60.9, 12.3; HRMS (Q-TOF, ESI) calcd
for C18H16NOþ [M ꢃ N2 þ H]þ 262.1226, found 262.1235.
4.3.2. 3-(Azido(phenyl)methyl)-5-(2-chlorophenyl)-2-methylfuran
(2b)
Yellow solid; 133.3 mg; 82% yield; mp 72e73 ꢀC; 1H NMR
4.2. General procedure for synthesis of 2-(1-alkynyl)-2-alken-1-
ones (1a-1w) [47]
(400 MHz, CDCl3)
d
7.74 (dd, J ¼ 8.0, 1.6 Hz, 1H), 7.32e7.30 (m, 5H),
7.25e7.16 (m, 2H), 7.09e7.05 (m, 1H), 6.93 (s, 1H), 5.58 (s, 1H), 2.28
(s, 3H); 13C NMR (100 MHz, CDCl3) 149.2, 148.5, 139.1, 130.8, 129.9,
128.93, 128.87, 128.2, 128.0, 127.5, 127.0, 126.9, 120.5, 111.5, 61.0,
12.3; HRMS (Q-TOF, ESI) calcd for C18H15ClNOþ [M ꢃ N2 þ H]þ
296.0837, found 296.0839.
4.3.3. 3-(Azido(phenyl)methyl)-5-(3-chlorophenyl)-2-methylfuran
(2c)
2-(1-Alkynyl)-2-alken-1-ones was prepared by
a slightly
Yellow solid; 153.7 mg; 95% yield; mp 34e35 ꢀC; 1H NMR
modified procedure. Bromine (1.92 g, 12.0 mmol, 1.2 equiv.) was
added dropwise to a solution of chalcone (10.0 mmol, 1.0 equiv.) in
DCM (10 mL) at 0 ꢀC. The mixture was stirred for 1 h at the same
temperature before quenching by the addition of a saturated
Na2S2O3 solution (20 mL). The aqueous phase was separated and
extracted with DCM (20 mL ꢂ 3). The organic phases were com-
bined and washed with brine. After drying with MgSO4, the solvent
was removed under vacuum. The residue was dissolved in DCM
(10 mL), then Et3N (1.69 mL, 12.0 mmol, 1.2 equiv.) was added, and
the mixture was heated at reflux for 1.5 h. After cooling to room
temperature, the solvent was removed under vacuum and water
(20 mL) was added. The aqueous phase was extracted with DCM
(20 mL ꢂ 3). The organic phases were combined and washed with
brine. After drying with MgSO4, the solvent was removed under
vacuum, and the crude product was purified by flash chromatog-
raphy to give the 2-Br-2-alken-1-one. Pd(Ph3P)4 (577.8 mg,
0.50 mmol, 0.05 equiv.) and CuI (190.5 mg, 1.0 mmol, 0.1 equiv.)
were added to a solution of 2-Br-2-alken-1-one (10.0 mmol, 1.0
equiv.) in THF (4.0 mL) and iPr2NH (4.20 mL, 30.0 mmol, 3.0 equiv.)
under Ar at room temperature. Phenylacetylene (1.10 mL,
10.0 mmol, 1.2 equiv.) was added by syringe. The mixture was
stirred for 2 h until TLC indicated completion of the reaction. The
mixture was diluted with EtOAc (20 mL), washed with 1N HCl and
brine, and dried with MgSO4. After removing the solvent under
vacuum, the crude product was purified by flash chromatography
to give 2-(1-alkynyl)-2-alken-1-one as a yellow solid.
(400 MHz, CDCl3)
(m, 5H), 7.24e7.22 (m, 1H), 7.17e7.15 (m, 1H), 6.47 (s, 1H), 5.62 (s,
1H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
150.9, 149.8, 139.1,
134.8, 132.3, 130.0, 128.9, 128.2, 127.2, 127.0, 123.6, 121.6, 120.7,
d 7.57e7.56 (m, 1H), 7.44e7.42 (m, 1H), 7.39e7.30
d
106.5, 60.8, 12.3; HRMS (Q-TOF, ESI) calcd for
C
18H15ClNOþ
[M ꢃ N2 þ H]þ 296.0837, found 296.0846.
4.3.4. 3-(Azido(phenyl)methyl)-5-(4-chlorophenyl)-2-methylfuran
(2d)
Yellow solid; 155.3 mg; 96% yield; mp 82e83 ꢀC; 1H NMR
(400 MHz, CDCl3)
(m, 3H), 6.45 (s, 1H), 5.63 (s, 1H), 2.37 (s, 3H); 13C NMR (100 MHz,
CDCl3) 151.3, 149.5, 139.1, 132.9, 129.1, 128.93, 128.87, 128.2, 126.9,
d 7.52e7.50 (m, 2H), 7.38e7.35 (m, 4H), 7.33e7.31
d
124.8, 120.7, 105.8, 60.8, 12.3; HRMS (Q-TOF, ESI) calcd for
C
18H15ClNOþ [M ꢃ N2 þ H]þ 296.0837, found 296.0839.
4.3.5. 3-(Azido(phenyl)methyl)-5-(2-fluorophenyl)-2-methylfuran
(2e)
Yellow solid; 111.8 mg; 73% yield; mp 55e56 ꢀC; 1H NMR
(400 MHz, CDCl3)
(m, 1H), 7.19e7.13 (m, 2H), 7.09e7.04 (m, 1H), 6.69 (d, J ¼ 3.5 Hz,
1H), 5.65 (s, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
158.5 (d,
d 7.79e7.75 (m, 1H), 7.38e7.36 (m, 4H), 7.32e7.29
d
J ¼ 250.5 Hz), 149.1, 146.4 (d, J ¼ 2.9 Hz), 139.1, 128.9, 128.3, 128.22,
128.15, 127.0, 125.7 (d, J ¼ 3.2 Hz), 124.3 (d, J ¼ 3.4 Hz), 120.7, 118.9
(d, J ¼ 12.0 Hz),116.0 (d, J ¼ 21.4 Hz),110.6 (d, J ¼ 11.7 Hz), 60.9,12.3;
19F NMR (376 MHz, CDCl3)
C
d
ꢃ113.91; HRMS (Q-TOF, ESI) calcd for
18H15FNOþ [M ꢃ N2 þ H]þ 280.1132, found 280.1138.
4.3. General procedure for synthesis of 3-azidomethylfurans (2a-
2w)
4.3.6. 3-(Azido(phenyl)methyl)-5-(4-fluorophenyl)-2-methylfuran
(2f)
Under an argon atmosphere, TMSN3 (1.5 eq.) and HOAc (1.0 eq.)
were added to
a
mixture of 2-(1-alkynyl)-2-alken-1-ones
1
Yellow solid; 156.2 mg; >99% yield; mp 58e59 ꢀC; 1H NMR
(0.50 mmol) and AgSbF6 (5 mol%) in a 15 mL Schlenk tube in
(400 MHz, CDCl3) d 7.59e7.55 (m, 2H), 7.40e7.38 (m, 4H), 7.35e7.31
Please cite this article as: L.-L. Qian et al., Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis,
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L.-L. Qian et al. / Tetrahedron xxx (xxxx) xxx
5
(m, 1H), 7.07e7.02 (m, 2H), 6.41 (s, 1H), 5.65 (s, 1H), 2.39 (s, 3H); 13
C
[M ꢃ N2 þ H]þ 338.1539, found 338.1541.
NMR (100 MHz, CDCl3)
d
162.2 (d, J ¼ 246.8 Hz), 151.5, 149.1, 139.2,
128.9, 128.2, 127.0 (d, J ¼ 3.3 Hz), 126.9, 125.3 (d, J ¼ 8.0 Hz), 120.5,
4.3.13. 1-(4-(4-(Azido(phenyl)methyl)-5-methylfuran-2-yl)phenyl)
115.8 (d, J ¼ 21.9 Hz), 105.0 (d, J ¼ 1.5 Hz), 60.8, 12.2; 19F NMR
ethan-1-one (2m)
Yellow solid; 140.7 mg; 85% yield; mp 64e65 ꢀC; 1H NMR
(376 MHz, CDCl3)
C
d
ꢃ114.38; HRMS (Q-TOF, ESI) calcd for
18H15FNOþ [M ꢃ N2 þ H]þ 280.1132, found 280.1146.
(400 MHz, CDCl3)
(m, 5H), 6.62 (s, 1H), 5.64 (s, 1H), 2.56 (s, 3H), 2.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) 197.3, 151.1, 150.5, 138.9, 135.4, 134.5, 128.9,
d 7.93e7.91 (m, 2H), 7.65e7.63 (m, 2H), 7.38e7.29
4.3.7. 3-(Azido(phenyl)methyl)-2-methyl-5-(3-(trifluoromethyl)
phenyl)furan (2g)
d
128.8, 128.2, 126.9, 123.2, 121.1, 107.9, 60.7, 26.6, 12.3; HRMS (Q-TOF,
Yellow solid; 160.2 mg; 90% yield; mp 37e38 ꢀC; 1H NMR
ESI) calcd for C20H18NO2þ [M ꢃ N2 þ H]þ 304.1332, found 304.1342.
(400 MHz, CDCl3)
2H), 7.43e7.33 (m, 5H), 6.58 (s, 1H), 5.67 (s, 1H), 2.42 (s, 3H); 13C
NMR (100 MHz, CDCl3) 150.82, 150.01, 139.05, 131.28, 131.25 (q,
d 7.86 (s, 1H), 7.77e7.75 (m, 1H), 7.49e7.46 (m,
4.3.14. 3-(Azido(phenyl)methyl)-2-methyl-5-(naphthalen-1-yl)
furan (2n)
d
Yellow oil; 93.3 mg; 55% yield; 1H NMR (400 MHz, CDCl3)
J ¼ 32.43 Hz), 129.24, 128.92, 128.25, 126.94, 126.56, 124.17 (d,
J ¼ 272.4 Hz), 123.74 (q, J ¼ 3.9 Hz), 120.87, 120.29 (q, J ¼ 3.9 Hz),
d
8.28e8.26 (m, 1H), 7.73e7.71 (m, 1H), 7.67e7.65 (m, 1H),
7.59e7.57 (m, 1H), 7.41e7.24 (m, 8H), 7.21e7.16 (m, 1H), 6.47 (s, 1H),
5.57 (s, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
151.7, 149.4,
106.70, 60.76, 12.3; 19F NMR (376 MHz, CDCl3)
d
ꢃ62.83; HRMS (Q-
TOF, ESI) calcd for C19H15F3NOþ [M ꢃ N2 þ H]þ 330.1100, found
d
330.1113.
139.3, 134.0, 130.2, 128.8, 128.6, 128.6, 128.2, 128.1, 127.0, 126.7,
126.0, 125.9, 125.5, 125.4, 120.2, 109.6, 61.0, 12.3; HRMS (Q-TOF, ESI)
calcd for C22H18NOþ [M ꢃ N2 þ H]þ 312.1383, found 312.1390.
4.3.8. 3-(Azido(phenyl)methyl)-2-methyl-5-(4-nitrophenyl)furan
(2h)
Yellow solid; 164.2 mg; 98% yield; mp 110e111 ꢀC; 1H NMR
4.3.15. 3-(Azido(phenyl)methyl)-2-methyl-5-(thiophen-2-yl)furan
(2o)
(400 MHz, CDCl3)
(m, 5H), 6.71 (s, 1H), 5.67 (s, 1H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) 151.6, 150.0, 146.4, 138.8, 136.2, 129.0, 128.4, 126.9, 124.4,
d 8.22e8.19 (m, 2H), 7.72e7.69 (m, 2H), 7.43e7.33
Under an argon atmosphere, TMSN3 (1.5 eq.) and HOAc (1.0 eq.)
d
were added to
a mixture of 2-(1-alkynyl)-2-alken-1-one 1o
123.7, 121.7, 109.5, 60.7, 12.5; HRMS (Q-TOF, ESI) calcd for
(0.50 mmol) and Pd(OAc)2 (10 mol%) in a 15 mL Schlenk tube in
toluene (5.0 mL). The mixture was stirred at 40 ꢀC until the sub-
strate 1o was consumed. Then the solvent was evaporated and the
crude product was directly purified by flash column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate) to give
the desired product 2o. Yellow solid; 114.5 mg; 78% yield; mp
C
18H15N2Oþ3 [M ꢃ N2 þ H]þ 307.1077, found 307.1088.
4.3.9. Ethyl 4-(4-(azido(phenyl)methyl)-5-methylfuran-2-yl)
benzoate (2i)
Colorless oil; 170.0 mg; 94% yield; 1H NMR (400 MHz, CDCl3)
d
8.02e8.00 (m, 2H), 7.65e7.63 (m, 2H), 7.39e7.32 (m, 5H), 6.61 (s,
64e65 ꢀC; 1H NMR (400 MHz, CDCl3)
7.33e7.29 (m,1H), 7.18e7.17 (m, 2H), 7.00e6.98 (m,1H), 6.32 (s,1H),
5.61 (s, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3)
148.7, 147.9,
139.1, 133.6, 128.9, 128.2, 127.7, 127.0, 124.1, 122.5, 120.4, 105.3, 60.8,
12.2; HRMS (Q-TOF, ESI) calcd for C16H14NOSþ [M ꢃ N2 þ H]þ
268.0791, found 268.0790.
d 7.39e7.34 (m, 4H),
1H), 5.68 (s, 1H), 4.37 (q, J ¼ 7.1 Hz, 2H), 2.39 (s, 3H), 1.39 (t,
J ¼ 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.4, 151.3, 150.3,
d
139.0, 134.4, 130.1, 128.9, 128.9, 128.2, 126.9, 123.1, 121.1, 107.6, 61.1,
60.8, 14.5, 12.4; HRMS (Q-TOF, ESI) calcd for
C
21H20NOþ3
[M ꢃ N2 þ H]þ 334.1438, found 334.1440.
4.3.10. 3-(Azido(phenyl)methyl)-2-methyl-5-(p-tolyl)furan (2j)
Yellow solid; 141.5 mg; 93% yield; mp 94e95 ꢀC; 1H NMR
4.3.16. 3-(Azido(phenyl)methyl)-5-cyclohexyl-2-methylfuran (2p)
Colorless oil; 50.0 mg; 34% yield; 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
(m,1H), 7.18e7.16 (m, 2H), 6.44 (s,1H), 5.66 (s,1H), 2.39 (s, 3H), 2.36
(s, 3H); 13C NMR (100 MHz, CDCl3)
152.5, 148.7, 139.3, 137.2, 129.4,
d 7.52e7.50 (m, 2H), 7.40e7.39 (m, 4H), 7.35e7.32
d
7.37e7.26 (m, 5H), 5.76 (s, 1H), 5.55 (s, 1H), 2.53e2.48 (m, 1H),
2.25 (s, 3H), 1.96e1.95 (m, 2H), 1.76e1.65 (m, 3H), 1.31e1.20 (m,
5H); 13C NMR (100 MHz, CDCl3)
159.4, 147.1, 139.6, 128.7, 127.9,
d
d
128.8, 128.1, 128.0, 127.0, 123.5, 120.3, 104.5, 60.9, 21.4, 12.3; HRMS
(Q-TOF, ESI) calcd for C19H18NOþ [M ꢃ N2 þ H]þ 276.1383, found
276.1392.
127.0, 118.2, 102.9, 61.1, 37.3, 31.6, 31.5, 26.2, 26.0, 12.0; HRMS (Q-
TOF, ESI) calcd for C18H22NOþ [M ꢃ N2 þ H]þ 268.1696, found
268.1697.
4.3.11. 3-(Azido(phenyl)methyl)-5-(4-methoxyphenyl)-2-
methylfuran (2k)
4.3.17. 3-(Azido(phenyl)methyl)-2,5-diphenylfuran (2q)
Yellow solid; 162.0 mg; 92% yield; mp 83e84 ꢀC; 1H NMR
Yellow solid; 128.7 mg; 81% yield; mp 38e39 ꢀC; 1H NMR
(400 MHz, CDCl3)
(m, 10H), 7.21e7.17 (m, 1H), 6.64 (s, 1H), 5.84 (s, 1H); 13C NMR
(100 MHz, CDCl3) 153.3, 150.3, 138.9, 130.3, 129.0, 128.9, 128.437,
d 7.64e7.62 (m, 2H), 7.58e7.56 (m, 2H), 7.38e7.25
(400 MHz, CDCl3)
(m, 1H), 6.79e6.76 (m, 2H), 6.24 (s, 1H), 5.52 (s, 1H), 3.69 (s, 3H),
2.26 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.0, 152.3, 148.3, 139.3,
d 7.44e7.41 (m, 2H), 7.27e7.26 (m, 4H), 7.22e7.20
d
d
128.3, 127.9, 127.3, 126.7, 124.0, 121.6, 107.0, 60.7; HRMS (Q-TOF, ESI)
128.8, 128.0, 126.9, 125.0, 123.7, 120.2, 114.1, 103.6, 60.9, 55.3, 12.2;
HRMS (Q-TOF, ESI) calcd for C19H18NOþ2 [M ꢃ N2 þ H]þ 292.1332,
found 292.1339.
calcd for C23H18NOþ [M ꢃ N2 þ H]þ 324.1383, found 324.1391.
4.3.18. 3-(Azido(phenyl)methyl)-2-(2-chlorophenyl)-5-phenylfuran
(2r)
4.3.12. 5-([1,10-Biphenyl]-4-yl)-3-(azido(phenyl)methyl)-2-
methylfuran (2l)
Yellow solid; 105.0 mg; 54% yield; mp 78e79 ꢀC; 1H NMR
Yellow solid; 182.4 mg; >99% yield; mp 83e84 ꢀC; 1H NMR
(400 MHz, CDCl3)
(m, 1H), 7.38e7.26 (m, 10H), 6.69 (s, 1H), 5.65 (s, 1H); 13C NMR
(100 MHz, CDCl3) 154.4, 148.3, 139.0, 134.6, 132.5, 130.8, 130.4,
130.3, 129.2, 128.8, 128.8, 128.1, 128.0, 127.1, 126.9, 124.1, 124.0,
d 7.70e7.68 (m, 2H), 7.53e7.51 (m, 1H), 7.46e7.43
(400 MHz, CDCl3)
(m, 2H), 7.30e7.29 (m, 4H), 7.27e7.23 (m, 2H), 6.43 (s, 1H), 5.56 (s,
1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3)
152.1, 149.3, 140.7,
d 7.59e7.57 (m, 2H), 7.53e7.49 (m, 4H), 7.36e7.33
d
d
140.0, 139.2, 129.6, 128.92, 128.85, 128.1, 127.5, 127.4, 127.0, 124.0,
105.5, 60.4; HRMS (Q-TOF, ESI) calcd for
C
23H17ClNOþ
120.6, 105.5, 60.9, 12.3; HRMS (Q-TOF, ESI) calcd for C24H20NOþ
[M ꢃ N2 þ H]þ 358.0993, found 358.0996.
Please cite this article as: L.-L. Qian et al., Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131327

6
L.-L. Qian et al. / Tetrahedron xxx (xxxx) xxx
4.3.19. 3-(Azido(phenyl)methyl)-2-(3-chlorophenyl)-5-phenylfuran
(2s)
TOF, ESI) calcd for C14H14NOþ [M þ H]þ 264.1383, found 264.1394.
Yellow solid; 138.7 mg; 72% yield; mp 88e89 ꢀC; 1H NMR
Declaration of competing interest
(400 MHz, CDCl3)
1H), 7.47e7.32 (m, 10H), 6.77 (s, 1H), 5.90 (s, 1H); 13C NMR
(100 MHz, CDCl3) 153.8, 148.5, 138.6, 135.0, 131.9, 130.2, 130.0,
129.1, 128.9, 128.5, 128.23, 128.21, 127.3, 126.5, 124.5, 124.2, 122.8,
d 7.75e7.73 (m, 2H), 7.68 (s, 1H), 7.52e7.50 (m,
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
d
107.3, 60.7; HRMS (Q-TOF, ESI) calcd for
C
23H17ClNOþ
[M ꢃ N2 þ H]þ 358.0993, found 358.0991.
Acknowledgments
4.3.20. 3-(Azido(phenyl)methyl)-2-(4-chlorophenyl)-5-phenylfuran
(2t)
This work was supported by the National Natural Science
Foundation of China (21572225, 21772194, 21971234).
Yellow solid; 130.2 mg; 67% yield; mp 91e92 ꢀC; 1H NMR
(400 MHz, CDCl3)
(m, 9H),7.33e7.30 (m, 1H), 6.74 (s, 1H), 5.88 (s, 1H); 13C NMR
(100 MHz, CDCl3) 153.5, 149.0, 138.6, 134.2, 130.1, 129.2, 129.1,
128.9, 128.7, 128.5, 128.1, 127.8, 127.3, 124.1, 122.1, 107.2, 60.7; HRMS
(Q-TOF, ESI) calcd for C23H17ClNOþ [M ꢃ N2 þ H]þ 358.0993, found
358.0997.
d 7.74e7.72 (m, 2H), 7.61e7.57 (m, 2H), 7.44e7.36
Appendix A. Supplementary data
d
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131327.
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Yellow solid; 115.2 mg; 63% yield; mp 62e63 ꢀC; 1H NMR
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(m, 7H), 7.15e7.13 (m, 3H), 6.59 (s, 1H), 5.80 (s, 1H), 2.27 (s, 3H); 13
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C
d
128.8, 128.3, 127.8, 127.5, 127.3, 126.7, 124.0, 121.0, 106.9, 60.7, 21.4;
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(m, 2H), 7.41e7.36 (m, 7H), 7.30e7.26 (m, 1H), 6.66 (s, 1H), 5.59 (s,
1H); 13C NMR (100 MHz, CDCl3)
153.5, 150.5, 137.5, 134.2, 130.2,
d 7.72e7.70 (m, 2H), 7.64e7.62 (m, 2H), 7.47e7.43
€
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d
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130.1, 129.1, 129.0, 128.9, 128.7, 128.5, 128.1, 126.7, 124.1, 121.1, 106.7,
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4.3.23. 4-Azido-2-phenyl-4,5,6,7-tetrahydrobenzofuran (2w)
Yellow oil; 98.0 mg; 82% yield; 1H NMR (400 MHz, CDCl3)
d
7.64e7.62 (m, 2H), 7.38e7.34 (m, 2H), 7.25e7.23 (m, 1H), 6.64 (s,
1H), 4.46 (t, J ¼ 3.7 Hz, 1H), 2.78e2.71 (m, 1H), 2.67e2.60 (m, 1H),
2.04e1.86 (m, 4H); 13C NMR (100 MHz, CDCl3)
153.0, 152.9, 130.9,
d
128.8, 127.4, 123.6, 117.9, 104.5, 55.0, 29.6, 23.0, 19.6; HRMS (Q-TOF,
ESI) calcd for C14H14NOþ [M ꢃ N2 þ H]þ 212.1070, found 212.1078.
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1H-1,2,3-triazole (4a)
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Yellow solid; 110.0 mg; 94% yield; mp 175e176 ꢀC; 1H NMR
ꢀ
ꢀ
(400 MHz, CDCl3)
d
7.84 (d, J ¼ 7.4 Hz, 2H), 7.77 (s, 1H), 7.59 (d,
J ¼ 7.4 Hz, 2H), 7.41e7.29 (m, 8H), 7.24e7.21 (m, 1H), 7.17e7.15 (d,
J ¼ 6.0 Hz, 2H), 7.00 (s, 1H), 6.44 (s, 1H), 2.29 (s, 3H); 13C NMR
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d 152.6, 150.1, 138.4, 130.6, 130.3, 129.1, 128.9,
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392.1758.
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d 7.58
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(d, J ¼ 7.4 Hz, 2H), 7.40 (d, J ¼ 7.4 Hz, 2H), 7.34e7.29 (m, 4H),
7.24e7.16 (m, 2H), 6.58 (s, 1H), 5.09 (s, 1H), 2.31 (s, 3H), 2.26 (br,
2H).; 13C NMR (100 MHz, CDCl3)
d
151.7, 147.2, 145.0, 131.0, 128.6,
128.6, 127.1, 126.9, 126.6, 125.7, 123.4, 105.1, 51.6, 12.2; HRMS (Q-
Please cite this article as: L.-L. Qian et al., Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131327

L.-L. Qian et al. / Tetrahedron xxx (xxxx) xxx
7
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Please cite this article as: L.-L. Qian et al., Rapid assembly of 3-azidomethylfurans from 2-(1-alkynyl)-2-alken-1-ones enabled by silver catalysis,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131327