Copper(I)-Catalyzed Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Azidoformates and Aryl Terminal Alkynes

Article abstract of DOI:10.1021/acs.joc.8b00022

The copper(I)-catalyzed azide-alkyne cycloaddition reaction has been extensively studied and widely applied in organic synthesis. However, the formation of 1,2,3-triazoles with electron-deficient azide has been a challenging problem. In this report, we ha

Full text of DOI:10.1021/acs.joc.8b00022

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Copper(I)-catalyzed synthesis of 1,4-disubstituted 1,2,3-
triazoles from azidoformates and aryl terminal alkynes
HeeJin Lee, Jae Kyun Lee, Sun-Joon Min, Hyeonglim Seo, Youngbok Lee, and Hakjune Rhee
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Mar 2018
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Copper(I)ꢀcatalyzed synthesis of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles
from azidoformates and aryl terminal alkynes
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Heejin Lee,† Jae Kyun Lee,‡ SunꢀJoon Min,§ Hyeonglim Seo,† Youngbok Lee,†,§ and Hakjune Rhee*,†,§
†Department of Bionanotechnology, Hanyang University, Sangnokꢀgu Hanyang Daehakꢀro 55,
Ansan, Gyeonggiꢀdo, 15588, Republic of Korea
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‡Center for NeuroꢀMedicine, Korea Institute of Science and Technology (KIST), Seongbukꢀgu Hwarangro 14ꢀgil 5,
Seoul 136ꢀ791, Republic of Korea
§Department of Applied Chemistry, Hanyang University, Sangnokꢀgu Hanyang Daehakꢀro 55, Ansan, Gyeonggiꢀdo,
15588, Republic of Korea
*Eꢀmail address: hrhee@hanyang.ac.kr
ABSTRACT
The copper(I)ꢀcatalyzed azideꢀalkyne cycloaddition (CuAAC) reaction has been extensively studied and widely
applied in organic synthesis. However, the formation of 1,2,3ꢀtriazoles with electronꢀdeficient azide has been a
challenging problem. In this report, we have demonstrated the formation of regioselective 1,4ꢀdisubstituted 1,2,3ꢀ
triazoles from various types of aryl terminal alkynes and azidoformates, which are electronꢀdeficient azides, using a
commercialized [Cu(CH3CN)4]PF6 copper(I) catalyst under mild conditions.
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Due to the discovery of the copperꢀcatalyzed azideꢀalkyne cycloaddition (CuAAC) reaction, the "click" reaction,1
the synthesis process for 1,2,3ꢀtriazoles has been significantly advanced. The classical thermal Huisgen
cycloaddition2 proceeds very slowly even at high temperatures, and produces a 1,4ꢀ and 1,5ꢀdisubstituted 1,2,3ꢀ
triazoles mixture. In 2002, the group of Medal3 and Sharpless4 discovered the copperꢀcatalyzed azideꢀalkyne
cycloaddition (CuAAC) reaction. In CuAAC, 1,2,3ꢀtriazole are formed with a copper(I) salt catalyst,3,4 which
improves both the selectivity and the reaction rate. Synthesis of 1,2,3ꢀtriazoles has been conducted in a wide range
of organic solvents, including water and at room temperature. Although these heterocycles do not take place
naturally, the 1,2,3ꢀtriazoles have various biological activities.5 The CuAAC reaction has found valuable
applications in a variety of fields.6
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Most CuAAC reactions are limited to alkyl or aryl azides. It is usually hard for an electronꢀdeficient azide to react
with terminal alkynes to produce a triazole ring in the presence of copper catalysts. To date, only a few research
groups have reported the 1,2,3ꢀtriazole formation with electronꢀdeficient azides such as Nꢀsulfonyl, Nꢀsulfamoyl,
and Nꢀcarbamoyl azides (Scheme 1).7ꢀ12
When Nꢀsulfonyl azides react with terminal alkynes in the presence of copper catalysts, they not only form
acyclic Nꢀcontaining compounds such as amidine, but they also form triazole rings. NꢀSulfonyl triazoles may then
undergo a ringꢀopening process via the ketenimine species occurring due to the loss of nitrogen gas from the Nꢀ
sulfonyl triazolyl copper intermediate.7
Next, Nꢀsulfamoyl triazoles are obtained when Nꢀsulfamoyl azides react with terminal alkynes under the specific
copper catalyst thiopheneꢀ2ꢀcarboxylate, i.e., Libeskind’s reagent,8 resulting in yields ranging from 82% to 95%.9
Pérez and his coꢀworkers developed a wellꢀdefined copperꢀbased catalytic system, [CuTpm*,Br(CH3CN)]BF4
(Tpm*,Br=tris(3,5ꢀdimethylꢀ4ꢀbromoꢀpyrazolyl)methane), which promotes the exclusive synthesis of Nꢀsulfonyl
triazoles in high yields under mild conditions.10 When this catalyst was used for the formation of Nꢀcarbonyl
triazoles from Nꢀcarbonyl azides, two types of oxazole derivatives were unexpectedly formed, instead of the
expected triazole rings.11 One was a 2,5ꢀdisubstituted oxazole, and the other was a trisubstituted oxazole. In further
studies, they solely investigated the synthesis of 2,5ꢀdisubstituted oxazole derivatives in presence of the
[CuTpa*]PF6 (Tpa=tris(pyrazolylmethyl)amine).12 Based on experimental data and mechanistic studies, this catalytic
system was a more active and selective. The intermediate nitrene copper species was formed via the loss of nitrogen
gas.13 They also observed the formation of Nꢀcarbamoyl triazoles from Nꢀcarbamoyl azides and terminal alkynes in
the presence of [CuTpa*]PF6. That is because the NꢀC(O)ꢀN moiety delocalizes the electronic density. The loss of
nitrogen gas and the formation of the copperꢀnitrene intermediate are interrupted because of the conjugation effect.14
In our study, we achieved direct formation of regioselective 1,4ꢀdisubstituted 1,2,3ꢀtriazoles from various
azidoformates and aryl terminal alkynes using the commercialized copper(I) catalyst, [Cu(CH3CN)4]PF6, under mild
conditions. This is the first report in the literature of the reaction between electronꢀdeficient aryl azidoformates and
aryl terminal alkynes.15
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Scheme 1. Developed synthetic methods using electronꢀdeficient azide for cycloaddition
There is a potential reaction pathway like as aryl or alkyl azides. This pathway forms the copperꢀacetylide
intermediate that leads to the formation of the triazolylꢀcuprate intermediate in equilibrium with the diazoimino
species. Because of the electronꢀwithdrawing nature of the group attached to the N3 moiety, the diazo derivative
loses N2 with concomitant formation of acyclic products. Therefore we consider the electronic characteristics of the
azidoformate. We hypothesized that the lone electron pair of the O within the NꢀC(O)ꢀO bond would help increase
the electron density due to conjugation effect. To explore this, we investigated the reaction of 1,2,3ꢀtriazole with
phenyl azidoformate (1a) and phenyl acetylene (2a) (Table 1). We first performed the synthesis of 1,2,3ꢀtriazole 3a
without the copper catalyst, and did not obtained the product (Table 1, entry 1). The same synthesis with various
commercialized copper catalysts were then tested (Table1, entries 2ꢀ10). As expected from the reactivity according
to oxidation states of Cu(I) and Cu(II), the reaction proceeded only in the presence of the copper(I) catalysts. The
copper(II) catalysts such as CuSO4ꢁ5H2O, Cu(OAc)2 and Cu(OSO2CF3)2 were inefficient (Table 1, entries 3ꢀ5).
Other copper catalysts, such as CuI, CuOAc, [Cu(phen)(PPh3)2]NO3ꢁ½CH2Cl2, and [Cu(PPh)3]Br were less effective
(Table 1, entries 6, 8, and 9). For the synthesis of 1,2,3ꢀtriazole from electronꢀdeficient azide, we primarily used
halogenated solvents. In our experiments, chloroform showed the highest yields. With other solvents, such as 1,2ꢀ
dichloroethane (DCE), 3a was obtained in just an 8% yield (Table 1, entry 11). The conversion of 3a is lower at
o
room temperature than at 40 C (Table 1, entry 12). Overall, the [3+2] cycloaddition reaction of 1a (1.0 mmol) and
2a (1.0 mmol) showed the best yield (92%) using the [Cu(CH3CN)4]PF6 (5 mol%) catalyst in CHCl3 (2.0 mL) in
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open air at 40 oC for 24 h (Table 1, entry 10).
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Table 1. Optimization of the reaction conditionsa
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Entry
Catalyst
Solvent Yieldb
1
2c
3
none
CuSO4•5H2O
CuSO4•5H2O
Cu(OAc)2
Cu(OSO2CF3)2
CuI
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
trace
trace
NR
NR
NR
3
4
5
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CuOAc
trace
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[Cu(phen)(PPh3)2]NO3• ½CH2Cl2 CHCl3
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[Cu(PPh)3]Br
CHCl3
CHCl3
DCE
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10
11
12d
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
92
8
CHCl3
4
a Reaction conditions: 1a (1mmol, 1.0 equiv.), 2a (1 mmol, 1.0 equiv.), catalyst (5 mol%), 40 oC, 24 h in chloroform
(2.0 mL, 0.5 M) under aerobic condition. b Yields were determined after the deprotection of carbamate moiety; NR =
No Reaction. c Na ascorbate (10 mol%) was added. d This reaction was performed at room temperature.
The structure of 3a16 and its configuration were determined using Xꢀray crystal structure analysis (see ESI), and
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the structure of 3g was confirmed by a 1D H selective NOESY spectrum (included in ESI). In addition, the H
NMR spectrum of 3a exhibited a sharp singlet peak at 8.54 ppm, which is the characteristic peak of the hydrogen at
position 5 in 1,4ꢀdisubstituted 1,2,3ꢀtriazoles (see ESI for more details).
Efficient conversion of 3a was observed with 5 mol% of [Cu(CH3CN)4]PF6. Therefore, the scope of the copper(I)ꢀ
catalyzed [3+2] cycloaddition reaction with various azidoformates 1 and terminal alkynes 2 was studied using the
established optimized reaction conditions (Table 1, entry 10). All results are shown in Scheme 2. The substrates
1aꢀi (Scheme 2; representing the azidoformate functional groups of phenyl 1a, electronꢀdonating 1b and 1c,
electronꢀwithdrawing 1d and 1e, and aliphatic 1fꢀi) resulted in the corresponding 1,2,3ꢀtriazoles 3aꢀi in relatively
high yields except 1d. In the case of 1d, a strong electronꢀwithdrawing nitro group, formation of the 1,2,3ꢀtriazole
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proved difficult. This is likely due to a similar mechanism as observed in previous reports using Nꢀcarbonyl azides.11
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Scheme 2. Scope study for azidoformatesa,b
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3a (92%)
3d (trace)d
3g (97%)
3b (91%)c
3e (60%)
3c (91%)c
3f (89%)
3i (92%)
3h (quant.)
a Reaction conditions: 1 (1 mmol, 1.0 equiv.), 2a (1 mmol, 1.0 equiv.), catalyst (5 mol%), 40 oC, 24 h in CHCl3 (2.0 mL, 0.5 M).
b Yields were determined after the deprotection of carbamate moiety. c This reaction was performed at 50 oC. d Compounds 3d
could not be isolated because of the extremely low conversion.
The reactions involving various aryl terminal alkynes also produced high yields (Scheme 3). The yield of 1,2,3ꢀ
triazole products 3nꢀq from electronꢀwithdrawing terminal alkynes was relatively lower than the other compounds.
o
Therefore, the reaction was kept at 50 C until the starting material disappeared. At this temperature, most of the
terminal alkynes had good reactivity and high yield for the synthesis of 1,2,3ꢀtriazoles. The 1,2,3ꢀtriazole products
3aꢀq were unstable, so it was difficult to isolate them through column chromatography. The reaction yields were
determined after the deprotection of carbamate moiety (Scheme 4). For the structural analysis of the desired
products, the crude products were purified by recrystallization with chloroform and hexane.
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Scheme 3. Scope study for terminal alkynesa,b
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3a (92%)
3l (85%)
3j (92%)
3k (90%)
O
O
N
N
N
Br
3m (85%)
3p (90%)c
3n (92%) c
3o (87%) c
3q (85%) c
a Reaction conditions: 1a (1 mmol, 1.0 equiv.), 2 (1 mmol, 1.0 equiv.), catalyst (5 mol%), 40 oC, 24 h in CHCl3 (2.0
mL, 0.5 M). b Yields were determined after the deprotection of carbamate moiety. c This reaction was performed at
50 oC.
Scheme 4. Deprotection of carbamate moiety
In conclusion, we have demonstrated the formation of regioselective 1,4ꢀdisubstituted 1,2,3ꢀtriazoles from various
types of aryl terminal alkynes and azidoformates, which are electronꢀdeficient azides, using a commercialized
[Cu(CH3CN)4]PF6 copper(I) catalyst under mild conditions. This methodology can be used to synthesize a range of
bioactive triazole derivatives with electronꢀdeficient groups.
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■ EXPERIMENTAL SECTION
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General information.
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All reagents and catalysts were purchased from commercial sources (Sigma Aldrich, TCI) and used without any
further purification, unless specifically mentioned. 1H and 13C NMR were recorded on a Bruker 400 MHz instrument
using CDCl3 as a NMR solvent. Infrared spectroscopic data were obtained using a Bruker FTꢀIR spectrometer.
HRMS analyses with EIꢀdouble focusing or FABꢀdouble focusing mode (JMSꢀ700) were performed at the Daegu
center of Korea Basic Science Institute. Xꢀray measurements were taken on a Rigaku RꢀAXIS RAPID
diffractometer using graphite monochromated MoꢀKa radiation.
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General Procedure for Azidoformate from Chloroformate (1aꢀ1i)17a
Chloroformate (20 mmol, 1.0 equimolar) was added to a wellꢀstirred suspension of NaN3 (1.2 equimolar) in
acetone (40 mL) at room temperature. After the reaction finished, the mixture was then poured into a celite pad. The
filtrate was collected and concentrated by rotary evaporation to isolate the product. In case of the synthesis of 4ꢀ
chlorophenyl azidoformate, the reaction was carried out with THF as the solvent.
Phenyl azidoformate (1a).17b Colorless oil; yield: 2.52 g (77%); 1H NMR (400 MHz, CDCl3): δ 7.40 (t, J = 8.0 Hz,
2H), 7.27 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 156.3, 150.6, 129.6, 126.6,
120.8; IR (neat): 2157, 1734, 1492, 1196, 953, 731 cmꢀ1.
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p-Tolyl azidoformate (1b).17c Colorless oil; yield: 3.46 g (98%); H NMR (400 MHz, CDCl3): δ 7.18 (d, J = 8.2
Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.5, 148.5, 136.4, 130.1, 120.6,
20.8; IR (neat): 2154, 1737, 1505, 1216, 1188, 737 cmꢀ1.
4-Methoxyphenyl azidoformate (1c).17d Colorless oil; yield: 3.55 g (92%); 1H NMR (400 MHz, CDCl3): δ 7.09 (d,
J = 9.2 Hz, 2H), 6.89 (d, J = 9.1 Hz, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.8, 156.7, 144.2, 121.8,
114.5, 55.5; IR (neat): 2152, 1736, 1504, 1238, 1195, 737 cmꢀ1.
4-Nitrophenyl azidoformate (1d).17e White solid; yield: 1.25 g (30%); 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J =
9.2 Hz, 2H), 7.40 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 155.7, 154.8, 145.8, 125.4, 121.9; IR (neat):
2170, 1736, 1522, 1470, 1209, 858, 743 cmꢀ1.
4-Chlorophenyl azidoformate (1e).17c White solid; yield: 786 mg (20%); 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J
= 9.0 Hz, 2H), 7.13 (d, J = 9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 156.2, 149.0, 132.1, 129.7, 122.3; IR (neat):
2156, 1736, 1486, 1208, 1084, 828, 735 cmꢀ1.
Ethyl azidoformate (1f).17f Colorless oil; yield: 1.45 g (63%); 1H NMR (400 MHz, CDCl3): δ 4.28 (q, J = 7.2 Hz,
2H), 1.33 (t, J =7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 157.5, 64.7, 14.1; IR (neat): 2133, 1725, 1368, 1219,
1021, 751 cmꢀ1.
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Amyl azidoformate (1g).17g Colorless oil; yield: 3.08 g (98%); 1H NMR (400 MHz, CDCl3): δ 4.21 (t, J = 6.7 Hz,
2H), 1.69 (quint, J = 7.0 Hz, 2H), 1.37ꢀ1.32 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 157.8,
69.0, 28.3, 27.9, 22.4, 14.1; IR (neat): 2133, 1727, 1219, 751 cmꢀ1.
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Isobutyl azidoformate (1h).17a Colorless oil; yield: 2.81 g (98%); H NMR (400 MHz, CDCl3): δ 4.00 (d, J = 6.7
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Hz, 2H), 2.00 (n, J = 6.7Hz, 1H), 0.96 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 157.6, 74.5, 27.7, 18.8;
cmꢀ1; IR (neat): 2136, 1726, 1221, 993, 752 cmꢀ1.
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Benzyl azidoformate (1i).17h Colorless oil; yield: 3.44 g (97%); H NMR (400 MHz, CDCl3): δ 7.37 (s, 2H), 5.22
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 157.5, 134.4, 128.9, 128.7, 128.6, 70.1; IR (neat): 2137, 1723, 1219, 958,
745, 695 cmꢀ1.
General Procedure for [3+2] Cycloaddtion of Alkyne and Azidoformate (3aꢀ3q)
The catalyst (18.6 mg, 0.05 mmol, 5 mol%) and azidoformate (1.0 mmol) were dissolved in Chloroform (2.0 mL)
in 10 mL roundꢀbottom flask. The alkyne (1.0 mmol) was added to the solution. The reaction mixture was stirred at
40ꢀ50 °C for 24h until the starting material disappeared. The reaction crude was extracted with dichloromethane and
distilledꢀwater. After drying over MgSO4, the mixture was poured into a celite pad. The solvent was evaporated
under reduced pressure. For the structural analysis of the desired products 3, the crude products were purified by
recrystallization with chloroform and hexane.
o
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Phenyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3a). White solid; yield: 244 mg (92%); m.p. 121ꢀ123 C; H
NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 7.94 (d, J = 7.0 Hz, 2H), 7.53ꢀ7.47 (m, 4H), 7.45ꢀ7.37 (m, 4H); 13C NMR
(100 MHz, CDCl3): δ 150.2, 148.4, 146.5, 130.2, 129.4, 129.3, 129.1, 127.5, 126.4, 121.1, 119.6; IR (neat): 3156,
1780, 1424, 1263, 1210, 742, 686 cmꢀ1; HRMS(EIꢀdouble focusing) m/z: [M]+ calcd. for C15H11N3O2 265.0851;
found 265.0849.
o
p-Tolyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3b). White solid; yield: 254 mg (91%); m.p. 139ꢀ140 C; 1H
NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.93 (d, J = 6.8 Hz, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.41 (td, J = 7.3, 1.2 Hz,
1H), 7.29ꢀ7.22(m, 4H), 2.40(s, 3H); 13C NMR (100 MHz, CDCl3): δ 148.2, 147.9, 146.4, 137.2, 130.4, 129.2, 129.1,
128.9, 126.2, 120.6, 119.4; IR (neat): 3148, 3064, 2920, 1775, 1423, 1230, 1002, 766 cmꢀ1; HRMS(EIꢀdouble
focusing) m/z: [M]+ calcd. for C16H13N3O2 279.1008; found 279.1006.
4-Methoxyphenyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3c). White solid; yield: 269 mg (91%); m.p. 152.7ꢀ
o
153 C; 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.0 Hz, 2H), 7.41 (t, J =
7.2 Hz, 1H), 7.28 (d, J = 9.1 Hz, 2H), 6,98 (d, J = 9.1 Hz, 2H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.3,
148.2, 146.6, 143.5, 129.2, 129.1, 128.9, 126.2, 121.8, 119.4, 114.8, 55.7; IR (neat): 3148, 2931, 1771, 1505, 1419,
1178, 994, 769 cmꢀ1; HRMS(EIꢀdouble focusing) m/z: [M]+ calcd. for C16H13N3O3 295.0957; found 295.0959.
4-Chlorophenyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3e). White solid; yield: 180 mg (60%); m.p. 122ꢀ123.8
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oC; H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.93 (d, J = 7.0 Hz, 2H), 7.51ꢀ7.40 (m, 5H), 7.33 (d, J = 8.9 Hz,
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2H); 13C NMR (100 MHz, CDCl3): δ 148.3, 148.3, 146.0, 132.9, 130.0, 129.3, 129.0, 128.7, 126.2, 122.3, 119.3; IR
(neat): 3150, 3077, 1777, 1428, 1260, 1070, 743 cmꢀ1; HRMS (EIꢀdouble focusing) m/z: [M]+ calcd. for
C15H10ClN3O2 299.0462; found 299.0465.
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Ethyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3f). White solid; yield: 193 mg (89%); m.p. 86.1ꢀ87 C; H NMR
(400 MHz, CDCl3): δ 8.39 (s, 1H), 7.89 (d, J = 7.0 Hz, 2H), 7.47 (t, J = 7.1 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 4.65 (q,
J = 7.2 Hz, 2H), 1.54 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 148.1, 147.8, 129.3, 129.3, 129.2, 126.4,
119.3, 66.2, 14.4; IR (neat): 3155, 2984, 1759, 1455, 1270, 1003, 762 cmꢀ1; HRMS (EIꢀdouble focusing) m/z: [M]+
calcd. for C11H11N3O2 217.0851; found 217.0853.
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Pentyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3g). White solid; yield: 252 mg (97%); m.p. 59.8ꢀ60 oC; H
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NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.89 (d, J = 7.0 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H),
4.57 (t, J = 6.8 Hz, 2H), 1.89 (qunit, J = 6.8 Hz, 2H), 1.50ꢀ1.36 (m, 4H), 0.94 (t, J = 7.1, 3H); 13C NMR (100 MHz,
CDCl3): δ = 148.0, 147.9, 129.3, 129.2, 127.0, 126.3, 119.3, 70.1, 28.3, 27.9, 22.4, 14.1; IR (neat): 3155, 2969, 1753,
1427, 1271, 1002, 761 cmꢀ1; HRMS (EIꢀdouble focusing) m/z: [M]+ calcd. for C14H17N3O2 259.1321; found
259.1320.
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Isobutyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3h). White solid; yield: 245 mg (Quant.); m.p. 101ꢀ103 C; H
NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.90 (d, J = 7.7 Hz, 2H), 7.49ꢀ7.38 (m, 3H), 4.36 (d, J = 6.8 Hz, 2H), 2.22
(n, J = 6.8 Hz, 1H), 1.08 (d, J = 6.7, 6H); 13C NMR (100 MHz, CDCl3): δ 147.8, 129.1, 129.0, 129.0, 126.1, 126.1,
119.0, 75.4, 27.8, 18.9; IR (neat): 3152, 2973, 1764, 1426, 1225, 1002, 759 cmꢀ1; HRMS (EIꢀdouble focusing) m/z:
[M]+ calcd. for C13H15N3O2 245.1164; found 245.1165.
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Benzyl 4-phenyl-1H-1,2,3-triazole-1-carboxylate (3i). White solid; yield: 257 mg (92%); m.p. 118ꢀ119 C; H
NMR (400 MHz, CDCl3): δ = 8.36 (s, 1H), 7.88 (d, J = 7.0 Hz, 2H), 7.54ꢀ7.51 (m, 2H), 7.48ꢀ7.37 (m, 6H), 5.58 (s,
2H); 13C NMR (100 MHz, CDCl3): δ 147.9, 147.6, 133.5, 129.4, 129.1, 129.1, 129.0, 129.0, 128.9, 126.2, 119.2,
71.1; IR (neat): 3134, 2974, 1768, 1404, 1210, 1009, 690 cmꢀ1; HRMS (EIꢀdouble focusing) m/z: [M]+ calcd. for
C16H13N3O2 279.1008; found 279.1012.
Phenyl 4-(p-tolyl)-1H-1,2,3-triazole-1-carboxylate (3j). White solid; yield: 257 mg (92%); m.p. 117.0 oC; 1H NMR
(400 MHz, CDCl3): δ 8.46 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 8.4 Hz, 2H), 7.40ꢀ7.35 (m, 3H), 7.29 (d, J =
8.0 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 150.0, 148.3, 146.3, 139.3, 130.0, 129.8, 129.8, 127.3,
126.1, 126.1, 120.9, 119.0, 21.4; IR (neat): 3134, 1769, 1405, 1204, 1022, 743 cmꢀ1; HRMS (EIꢀdouble focusing)
m/z: [M]+ calcd. for C16H13N3O2 279.1008; found 279.1008.
Phenyl 4-(4-methoxyphenyl)-1H-1,2,3-triazole-1-carboxylate (3k). White solid; yield: 266 mg (90%); m.p. 162ꢀ
163 oC; 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.52ꢀ7.48 (m, 2H), 7.40ꢀ7.36 (m, 3H),
7.01 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.4, 150.0, 148.1, 146.3, 130.0, 127.6,
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127.3, 121.5, 120.9, 118.3, 114.5, 55.4; IR (neat): 3150, 2958, 1777, 1358, 1189, 1112, 994, 752 cmꢀ1; HRMS (EIꢀ
double focusing) m/z: [M]+ calcd. for C16H13N3O3 295.0957; found 295.0959.
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Phenyl 4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazole-1-carboxylate (3l). Ivory solid; yield: 273 mg (85%); m.p. 112ꢀ
114 oC; 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.52ꢀ7.47 (m, 4H), 7.40ꢀ7.35 (m, 3H),
1.36 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 152.5, 150.0, 148.2, 146.3, 130.0, 127.3, 126.1, 126.0, 126.0, 121.0,
119.0, 32.8, 31.3; IR (neat): 3175, 2963, 1760, 1427, 1222, 989, 743 cmꢀ1; HRMS (EIꢀdouble focusing) m/z: [M]+
calcd. for C19H19N3O2 321.1477; found 321.1480.
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Phenyl 4-(4-bromophenyl)-1H-1,2,3-triazole-1-carboxylate (3m). White solid; yield: 293 mg (85%); m.p. 163ꢀ165
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oC; H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.53ꢀ7.48 (m,
2H), 7.40ꢀ7.35 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 150.0, 147.2, 146.1, 132.3, 130.0, 127.8, 127.7, 127.4,
123.4, 120.9, 119.6; IR (neat): 3148, 1779, 1427, 1259, 811, 741 cmꢀ1; HRMS (EIꢀdouble focusing) m/z: [M]+ calcd.
for C15H10BrN3O2 342.9956; found 342.9958.
Phenyl 4-(3,4-dichlorophenyl)-1H-1,2,3-triazole-1-carboxylate (3n). White solid; yield: 307 mg (92%); m.p.
o
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137.5ꢀ139 C; H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H),
7.57ꢀ7.48 (m, 3H), 7.41ꢀ7.35 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 166.2, 149.9, 146.1, 133.5, 133.3, 131.1,
130.0, 128.9, 128.0, 127.5, 125.3, 120.8, 120.0; IR (neat): 3134, 1784, 1426, 1226, 1011, 749 cmꢀ1; HRMS (EIꢀ
double focusing) m/z: [M]+ calcd. for C15H9Cl2N3O2 333.0072; found 333.0072.
Phenyl 4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole-1-carboxylate (3o). White solid; yield: 290 mg (87%);
o
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m.p. 130ꢀ132 C; H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H),
7.54ꢀ7.48 (m, 2H), 7.41ꢀ7.35 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 149.9, 146.8, 146.1, 132.3, 131.1 (q, J = 32.5
Hz), 130.0, 127.5, 126.5, 126.1 (q, J = 3.8 Hz), 123.9 (q, J = 270.5 Hz), 120.9, 120.4; IR (neat): 3142, 1785, 1427,
1261, 1123, 1000, 746 cmꢀ1; HRMS (EIꢀdouble focusing) m/z: [M]+ calcd. for C16H10F3N3O2 333.0725; found
333.0722.
Phenyl 4-(4-chlorophenyl)-1H-1,2,3-triazole-1-carboxylate (3p). White solid; yield: 270 mg (90%); m.p. 164.8ꢀ
165 oC; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.52ꢀ7.47 (m, 4H), 7.40ꢀ7.35 (m, 3H);
13C NMR (100 MHz, CDCl3): δ 149.9, 147.1, 146.1, 135.1, 130.0, 129.3, 127.5, 127.4, 121.1, 120.9, 119.5; IR
(neat): 3149, 1773, 1420, 1226, 992, 764 cmꢀ1; HRMS(FABꢀdouble focusing) m/z: [M+H]+ calcd. for
C15H10ClN3O2+H 300.0540; found 300.0542.
Phenyl 4-(4-(methoxycarbonyl)phenyl)-1H-1,2,3-triazole-1-carboxylate (3q). White solid; yield: 275 mg (85%);
o
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m.p. 183ꢀ185 C; H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.16 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8,5 Hz, 2H),
7.53ꢀ7.49 (m, 2H), 7.41ꢀ7.37 (m, 3H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.6, 149.9, 147.2, 133.1,
130.4, 130.0, 127.4, 126.1, 120.9, 120.9, 120.4; IR (neat): 1781, 1429, 1411, 1297, 1110, 1002, 753 cmꢀ1;
HRMS(FABꢀdouble focusing) m/z: [M+H]+ calcd. for C17H13N3O4+H 324.0984; found 324.0986.
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General Procedure for 1Hꢀ1,2,3ꢀTriazoles (4aꢀ4i)
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The reaction yields were determined after the deprotection of carbamate moiety. The crude mixture was reacted
with KOH in methanol at room temperature overnight and was quenched with HCl aqueous solution to produce the
free triazole. Compounds 4 were confirmed according to literature.18
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4-Phenyl-1H-1,2,3-triazole (4a).18a White solid; yield: 134 mg (92%); 1H NMR (400 MHz, DMSOꢀd6+TFA 1
drop): δ 8.34 (s, 1H), 7.86 (d, J = 7.1 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H).
4-(p-Tolyl)-1H-1,2,3-triazole (4b).18a White solid; yield: 146 mg (92%); 1H NMR (400 MHz, DMSOꢀd6+TFA 1
drop): δ 8.27 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 2.32 (s, 3H).
4-(4-Methoxyphenyl)-1H-1,2,3-triazole (4c).18a White solid; yield: 158 mg (90%); 1H NMR (400 MHz, DMSOꢀ
d6+TFA 1 drop): δ 8.22 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H).
4-(4-(tert-Butyl)phenyl)-1H-1,2,3-triazole (4d).18b White solid; yield: 171 mg (85%); 1H NMR (400 MHz, DMSOꢀ
d6+TFA 1 drop): δ 8.25 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 1.29 (s, 9H).
4-(4-Bromophenyl)-1H-1,2,3-triazole (4e).18a White solid; yield: 190 mg (85%); 1H NMR (400 MHz, DMSOꢀ
d6+TFA 1 drop): δ 8.40 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H).
4-(3,4-Dichlorophenyl)-1H-1,2,3-triazole (4f).18c White solid; yield: 197 mg (92%); 1H NMR (400 MHz, DMSOꢀ
d6+TFA 1 drop): δ 8.51 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.0, 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H).
4-(4-(Trifluoromethyl)phenyl)-1H-1,2,3-triazole (4g).18d White solid; yield: 185 mg (87%); 1H NMR (400 MHz,
DMSOꢀd6+TFA 1 drop): δ 8.54 (s, 1H), 8.10 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H).
4-(4-Chlorophenyl)-1H-1,2,3-triazole (4h).18a White solid; yield: 162 mg (90%); 1H NMR (400 MHz, DMSOꢀ
d6+TFA 1 drop): δ 8.39 (s, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H).
Methyl 4-(1H-1,2,3-triazol-4-yl)benzoate (4i).18a White solid; yield: 173 mg (85%); 1H NMR (400 MHz, DMSOꢀ
d6+TFA 1 drop): δ 8.51 (s, 1H), 8.05ꢀ8.00 (m, 4H), 3.86 (s, 3H).
■ ASSOCIATED CONTENT
Supporting Information
Supporting Information is available free of charge on the ACS Publications website at DOI: Xꢀray crystal structure
of compound 3a, 1H and 13C NMR spectra of products, and NOE difference experiment for compound 3g.
■ AUTHOR INFORMATION
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Corresponding Author
*Eꢀmail: hrhee@hanyang.ac.kr
Notes
The authors declare no competing financial interest.
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■ ACKNOWLEDGEMENTS
This research was supported by the Basic Science Research Program administered through the National Research
Foundation of Korea (NRF), funded by the Ministry of Education (2015R1D1A1A09058536) and by the Korean
Ministry of Education through the BK21ꢀPlus Project of the Hanyang University Graduate Program.
■ REFERENCES
1. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Function from a Few
Good Reactions. Angew. Chem., Int. Ed. 2001, 40, 2004ꢀ2021. (b) Meldal, M.; Tornøe, C. W. Cuꢀ
Catalyzed AzideꢀAlkyne Cycloaddition. Chem. Rev. 2008, 108, 2952–3015. (c) Hein, J. E.; Fokin, V. V.
CopperꢀCatalyzed AzideꢀAlkyne Cycloaddition (CuAAC) and beyond: New Reactivity of Copper(I)
Acetylides. Chem. Soc. Rev. 2010, 39, 1302ꢀ1315. (d) Liang, L. Y.; Astruc, D. The Copper(I)ꢀCatalyzed
AlkyneꢀAzide Cycloaddition (CuAAC) “Click” Reaction and its Applications. An overview. Coord.
Chem. Rev. 2011, 255, 2933–2945. (e) Haldon, E.; Nicasio, M. C.; Pérez, P. J. CopperꢀCatalysed Azide–
Alkyne Cycloadditions (CuAAC): an update. Org. Biomol. Chem. 2015, 13, 9528ꢀ9550.
2. (a) Huisgen, R. 1,3ꢀDipolar Cycloadditions. Past and Future. Angew. Chem., Int. Ed. Engl. 1963, 2, 565ꢀ
598. (b) Huisgen, R. Kinetics and Mechanism of 1,3ꢀDipolar Cycloadditions. Angew. Chem., Int. Ed. Engl.
1963, 2, 633ꢀ645. (c) Huisgen, R. Kinetics and Reaction Mechanisms: Selected Examples from the
Experience of Forty Years. Pure Appl. Chem. 1989, 61, 613ꢀ628.
3. Tornøe, C. W.; Christensen, C.; Meldal, M. P. Peptidotriazoles on Solid Phase: [1,2,3]ꢀTriazoles by
Regiospecific Copper(I)ꢀCatalyzed 1,3ꢀDipolar Cycloadditions of Terminal Alkynes to Azides. J. Org.
Chem. 2002, 67, 3057ꢀ3064.
4. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen Cycloaddition
Process: Copper(I)‐Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem.,
Int. Ed. 2002, 41, 2596ꢀ2599.
5. Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Click Chemistry
Reactions in Medicinal Chemistry: Applications of the 1,3ꢀDipolar Cycloaddition between Azides and
Alkynes. Med. Res. Rev. 2008, 28, 278ꢀ308.
6. (a) Hein, C. D.; Liu, X.ꢀM.; Wang, D. Click Chemistry, A Powerful Tool for Pharmaceutical Sciences.
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7
8
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Pharm. Res. 2008, 10, 2216ꢀ2230. (b) Moorhouse, A. D.; Moses, J. E. Click Chemistry and Medicinal
Chemistry: A Case of “CycloꢀAddiction”. Chem. Med. Chem. 2008, 3, 715ꢀ723. (c) Agalave, S. G.;
Maujan, S. R.; Pore, V. S. Click Chemistry: 1,2,3ꢀTriazoles as Pharmacophores. Chem. Asian J. 2011, 6,
2696ꢀ2718. (d) Lallana, E.; FernandezꢀTrillo, F.; SousaꢀHerves, A.; Riguera, R.; FernandezꢀMegia, E.
Click Chemistry with Polymers, Dendrimer, Hydrogels, for Drug Delivery. Pharm. Res. 2012, 29, 902ꢀ
921. (e) Yang, M.; Li, J.; Chen, P. R. Transition MetalꢀMediated Bioorthogonal Protein Chemistry in
Living Cells. Chem. Soc. Rev. 2014, 43, 6511ꢀ6526.
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7. (a) Bae, I.; Han, H.; Chang, S. Highly Efficient OneꢀPot Synthesis of NꢀSulfonylamidines by Cuꢀ
Catalyzed ThreeꢀComponent Coupling of Sulfonyl Azide, Alkyne, and Amine. J. Am. Chem. Soc. 2005,
127, 2038ꢀ2039. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. CopperꢀCatalyzed Hydrative Amide
Synthesis with Terminal Alkyne, Sulfonyl Azide, and Water. J. Am. Chem. Soc. 2005, 127, 16046ꢀ16047.
(c) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Practical Synthesis of Amides from In Situ Generated
Copper(I) Acetylides and Sulfonyl Azides. Angew. Chem., Int. Ed. 2006, 45, 3154ꢀ3157. (d) Whiting, M.;
Fokin, V. V. Copper‐Catalyzed Reaction Cascade: Direct Conversion of Alkynes into N‐Sulfonylazetidin‐
2‐imines. Angew. Chem., Int. Ed. 2006, 45, 3157ꢀ3161. (e) Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K.
B.; Fokin, V. V.; Chang, S. Mechanistic Studies on the CuꢀCatalyzed ThreeꢀComponent Reactions of
Sulfonyl Azides, 1ꢀAlkynes and Amines, Alcohols, or Water: Dichotomy via a Common Pathway. J. Org.
Chem. 2008, 73, 5520ꢀ5528. (f) Wang, F.; Fu, H.; Jiang, Y.; Zhaoa, Y. Copper‐Catalyzed Cycloaddition of
Sulfonyl Azides with Alkynes to Synthesize N‐Sulfonyltriazoles ‘on Water’ at Room Temperature. Adv.
Synth. Catal. 2008, 350, 1830ꢀ1834. (g) Kim, S. H.; Park, S. H.; Choi, J. H.; Chang, S. Tandem Cuꢀ
Catalyzed Ketenimine Formation and Intramolecular Nucleophile Capture: Synthesis of 1,2ꢀDihydroꢀ2ꢀ
iminoquinolines from 1ꢀ(oꢀAcetamidophenyl)propargyl Alcohols. Chem. Asian J. 2011, 6, 2618ꢀ2634.
8. Allred, G. D.; Libeskind, L. S. CopperꢀMediated CrossꢀCoupling of Organostannanes with Organic
Iodides at or below Room Temperature. J. Am. Chem. Soc. 1996, 118, 2748ꢀ2749.
9. Culhane, J. C.; Fokin, V. V. Synthesis and Reactivity of Sulfamoyl Azides and 1ꢀSulfamoylꢀ1,2,3ꢀ
triazoles. Org. Lett. 2011, 13, 4578ꢀ4580.
10. Cano, I.; Nicasio, M. C.; Pérez, P. J. Copper(I) Complexes as Catalysts for the Synthesis of NꢀSulfonylꢀ
1,2,3ꢀtriazoles from NꢀSulfonylazides and Alkynes. Org. Biomol. Chem. 2010, 8, 536ꢀ538.
11. Cano, I.; Álvarez, E.; Nicasio, M. C.; Pérez, P. J. Universal Peptidomimetics. J. Am. Chem. Soc. 2011,
133, 191ꢀ193.
12. Haldón, E.; Besora, M.; Cano, I.; Cambeiro, X. C.; Pericàs, M. A.; Maseras, F.; Nicasio, M. C.; Pérez, P.
J. Reaction of Alkynes and Azides: Not Triazoles Through Copper–Acetylides but Oxazoles Through
Copper–Nitrene Intermediates. Chem. Eur. J. 2014, 20, 3463ꢀ3474.
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13. Himo, F.; Demko, Z. P.; Noodleman, N.; Sharpless, K. B. Mechanisms of Tetrazole Formation by
Addition of Azide to Nitriles. J. Am. Chem. Soc. 2002, 124, 12210ꢀ12216.
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14. Haldón, E.; Álvarez, E.; Nicasio, M. C.; Pérez, P. J. 1,2,3ꢀTriazoles from Carbonyl Azides and Alkynes:
9
Filling the Gap. Chem. Commun. 2014, 50, 8978ꢀ8981.
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15. For alkyl azidoformates, there have previously been reported the related nonꢀcatalyzed version (four
examples) and the CuAAC reactions (only one example each): See, (a) Huisgen, R.; Blaschke, H. 1.3ꢀ
Cycloadditionen des äthoxycarbonylꢀazens an Alkine. Tetrahedron Lett. 1964, 1409ꢀ1413. (b) Hein, J. E.;
Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Copper(I)ꢀCatalyzed Cycloaddition of
Organic Azides and 1ꢀIodoalkynes. Angew. Chem., Int. Ed. Engl. 2009, 48, 8018ꢀ8021. (c) Gommermann,
N.; Gehrig, A.; Knochel, P. UltrasoundꢀPromoted CopperꢀCatalyzed Azide–Alkyne Cycloaddition. Synlett
2005, 2796ꢀ2798.
16. CCDC 1562183 contains the supplementary crystallographic data for this paper. The data were registered
to The Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk/get structures).
17. (a) Moon, S. ꢀY.; Kim, U. B.; Sung, D. ꢀB.; Kim, W. ꢀS. A Synthetic Approach to NꢀAryl Carbamates via
CopperꢀCatalyzed Chan–Lam Coupling at Room Temperature. J. Org. Chem. 2015, 80, 1856ꢀ1865. (b)
Frøyen, P. A Particularly Convenient OneꢀPot Synthesis of NꢀAlkoxycarbonyl NꢀAcyl and NꢀAroyl
Substituted Iminophosphoranes; Improved Preparation of Azidoformates, Aroyl and Alkanoyl Azides; An
Alternative Route to Complex Amides. Phosphorus Sulfur Silicon Relat. Elem. 1993, 78, 161ꢀ171. (c)
Krichekdorf, H. R. Reaktionen mit Silylaziden; 3. Mitteilung. Azidoameisensäureester und NꢀAcylꢀ
phosphinimine. Synthesis, 1972, 695ꢀ697. (d) Wu, P. ꢀL.; Su, C. ꢀH.; Gu, Y. ꢀJ. A Facile Synthesis of
Azidoformate via Chloroformate. J. Chin. Chem. Soc. 2000, 47, 271ꢀ274. (e) Rhouati, S.; Bernou, A.
Intramolecular Cyclization of Aryl Nitrenes. J. Soc. Alger. Chim. 1992, 2, 166ꢀ173. (f) Holzinger, M.;
Abraham, J.; Whelan, P; Graupner, R.; Ley, L.; Hennrich, F.; Kappes, M.; Hirsch, A. Functionalization of
SingleꢀWalled Carbon Nanotubes with (Rꢀ) Oxycarbonyl Nitrenes. J. Am. Chem. Soc. 2003, 125, 8566ꢀ
8580. (g) Lei, G.; Xu, H.; Xu, X. Staudinger Reaction Between Bicyclic Phosphites and Azides.
Phosphorus Sulfur Silicon Relat. Elem. 1992, 66, 101ꢀ106. (h) Zeng, H.; Tian, Q.; Shao, H. PEGꢀ400
Promoted Nucleophilic Substitution Reaction of Halides into Organic Azides under Mild Conditions.
Green Chem. Lett. Rev. 2011, 4, 281ꢀ287.
18. (a) Zhang, W.; Kuang, C.; Yang, Q. PalladiumꢀCatalyzed OneꢀPot Synthesis of 4ꢀArylꢀ1Hꢀ1,2,3ꢀtriazoles
from antiꢀ3ꢀArylꢀ2,3ꢀdibromopropanoic Acids and Sodium Azide. Synthesis 2010, 283ꢀ287. (b) Kalisiak,
J.; Sharpless, K. B.; Fokin, V. V. Efficient Synthesis of 2ꢀSubstitutedꢀ1,2,3ꢀtriazoles. Org. Lett. 2008, 10,
3171ꢀ3174. (c) Cohrt, A. E.; Jensen, J. F.; Nielsen, T. E. Traceless Azido Linker for the SolidꢀPhase
Synthesis of NHꢀ1,2,3ꢀTriazoles via CuꢀCatalyzed Azide−Alkyne Cycloaddition Reactions. Org. Lett.
2010, 12, 5414ꢀ5417. (d) Jiang, Y.; Kuang, C.; Yang, Q. Copper(I) IodideꢀCatalyzed Synthesis of 4ꢀArylꢀ
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1Hꢀ1,2,3ꢀtriazoles from antiꢀ3ꢀArylꢀ2,3ꢀdibromopropanoic Acids and Sodium Azide. Synthesis 2010,
4256ꢀ4260.
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