Synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazoles mediated by in situ generated copper(I) catalyst and electrophilic triiodide ion

Article abstract of DOI:10.1021/jo300841c

Mixing copper(II) perchlorate and sodium iodide solutions results in copper(I) species and the electrophilic triiodide ions, which collectively mediate the cycloaddition reaction of organic azide and terminal alkyne to afford 5-iodo-1,4-disubstituted-1,2,3-triazoles. One molar equivalent of an amine additive is required for achieving a full conversion. Excessive addition of the amine compromises the selectivity for 5-iodo-1,2,3-triazole by promoting the formation of 5-proto-1,2,3-triazole. Based on preliminary kinetic and structural evidence, a mechanistic model is formulated in which a 5-iodo-1,2,3-triazole is formed via iodination of a copper(I) triazolide intermediate by the electrophilic triiodide ions (and possibly triethyliodoammonium ions). The experimental evidence explains the higher reactivity of the in situ generated copper(I) species and triiodide ion in the formation of 5-iodo-1,2,3-triazoles than that of the pure forms of copper(I) iodide and iodine.

Full text of DOI:10.1021/jo300841c

Article
pubs.acs.org/joc
Synthesis of 5-Iodo-1,4-disubstituted-1,2,3-triazoles Mediated by
in Situ Generated Copper(I) Catalyst and Electrophilic Triiodide Ion
Wendy S. Brotherton, Ronald J. Clark, and Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, United States
S
* Supporting Information
ABSTRACT: Mixing copper(II) perchlorate and sodium iodide solu-
tions results in copper(I) species and the electrophilic triiodide ions,
which collectively mediate the cycloaddition reaction of organic azide and
terminal alkyne to afford 5-iodo-1,4-disubstituted-1,2,3-triazoles. One
molar equivalent of an amine additive is required for achieving a full
conversion. Excessive addition of the amine compromises the selectivity
for 5-iodo-1,2,3-triazole by promoting the formation of 5-proto-1,2,3-triazole. Based on preliminary kinetic and structural
evidence, a mechanistic model is formulated in which a 5-iodo-1,2,3-triazole is formed via iodination of a copper(I) triazolide
intermediate by the electrophilic triiodide ions (and possibly triethyliodoammonium ions). The experimental evidence explains
the higher reactivity of the in situ generated copper(I) species and triiodide ion in the formation of 5-iodo-1,2,3-triazoles than
that of the pure forms of copper(I) iodide and iodine.
alkenes, and terminal alkynes via Suzuki, Heck, and Sonogashira
reactions, respectively.12,14 Functionalization of 5-iodotriazolyl-
containing macrocycles via palladium-catalyzed means was
also achieved.18 Additionally, Rowan and co-workers applied a
palladium-mediated approach to fusing two 5-iodotriazolyl
moieties, which afforded compounds of extended aromaticity.19
On the supramolecular chemistry front, 5-iodotriazolium has
become an attractive component in aiding anion recognition.17,20
Our investigation in 5-iodotriazole synthesis started with the
observation that the CuI-catalyzed cycloaddition of 2-picolyl
azide with 1-iodoalkynes gave 5-iodotriazoles without an extra
assisting ligand, which was considered essential in the original
report by Fokin et al. A “one-pot” method was subsequently
developed that allowed for the formation of 5-iodotriazoles
from terminal alkynes without the separate synthesis of the
1-iodoalkyne substrates. In our method, copper(I) catalyst and
INTRODUCTION
■
The copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC)1,2
affords 1,2,3-triazoles under a vast array of conditions in high
yields. It has, since its discovery, become one of the most
applied organic reactions in this century in many areas of
research.3,4 Expansion of CuAAC into the synthesis of 5-iodo-
1,2,3-triazoles (5-iodotriazole in the following text) and, by
further elaboration, 1,4,5-trisubstituted 1,2,3-triazoles, has
recently garnered much interest.5 5-Iodotriazole was observed
as a byproduct in CuAAC reactions where copper(I) iodide
(CuI) was used as a catalyst.6,7 Wu et al.8 reported the first
synthesis of 5-iodotriazole through a “one-pot” reaction strategy
(Scheme 1A). Based on the mechanism of the CuAAC reaction
proposed by Fokin et al.,1,4 Wu and co-workers suggested that
the copper(I) triazolide intermediate could be trapped by the
electrophilic iodine monochloride (ICl) to afford 5-iodotriazole.
Other one-pot methods have since been developed on the basis of
the same mechanistic hypothesis to prepare 5-iodotriazoles (e.g.,
see Scheme 1B), and other 1,4,5-trisubstituted triazoles.9−11
More recently, Hein, Fokin, and co-workers reported the
synthesis of 5-iodotriazole from the CuI-catalyzed cycloaddition
of 1-iodoalkyne and organic azide (iCuAAC)13 in the presence
of an assisting ligand such as tris((1-benzyl-1H-1,2,3-triazolyl)-
methyl)amine (TBTA) or tris((1-tert-butyl-1H-1,2,3-triazolyl)-
methyl)amine (TTTA, Scheme 1C).12 With low catalyst loadings
(5 mol %) and short reaction times (6 h), 5-iodotriazoles were
produced in good yields (73−99%). Further optimization led to
a “one-pot” method that entailed the sequential formations of
1-iodoalkyne and 5-iodotriazole.13
−
the electrophilic triiodide ion (I3 ) are formed in situ via the
reduction of copper(II) salts by NaI (Scheme 2, right). The
−
copper(I) species catalyzes the iCuAAC reaction, while I3
(and likely also triethyliodoammonium ion), rather than iodine
(I2), iodinates the copper(I) triazolide intermediate to afford a
5-iodotriazole. This in situ approach to producing copper(I)
species mirrors the Fokin/Sharpless CuAAC conditions where
the copper(I) catalyst emerges via the reduction of CuSO4 by
sodium ascorbate (Scheme 2, left). A mechanistic model is
presented based on the kinetic and structural evidence.
RESULTS AND DISCUSSION
■
“Assisting Ligand-Free” Synthesis. 1-Iodoalkynes were
prepared following a procedure described in the literature.21 The
reaction between 2-picolyl azide and 1-iodo-2-phenylethyne
We are motivated to prepare 5-iodotriazoles by their pro-
mises as substrates of palladium-catalyzed cross-coupling
reactions12−14 and subjects to study halogen bonding15,16 in
the context of supramolecular chemistry.17 As demonstrated
by others, 5-iodotriazoles could couple with arylboronic acids,
Received: May 2, 2012
© XXXX American Chemical Society
A
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Scheme 1. Selected Methods To Prepare 5-Iodotriazoles: (A) Reaction Reported by Wu et al.8 in Which ICl is the Iodinating
Agent; (B) Reaction Reported by Zhang et al.9 in Which the Iodinating Agent Results from the Reaction of NBS and CuI; (C)
Reaction Reported by Hein, Fokin, et al.12
Scheme 2. Methods of in Situ Copper(I) Generation, Which
Leads to the Formation of 5-Prototriazoles (Left) and
5-Iodotriazoles (Right), Respectively
catalyst and iodinating reagent from readily available copper(II)
salts and NaI.25
−
(a) In Situ Generation of CuI and I2 (and I3 ). More than
half a century ago, Kauffman and Pinnell26 found that
copper(II) sulfate reacts with potassium iodide to afford
copper(II) iodide (eq 1), which decomposes immediately to
yield CuI and I2 (eq 2).
CuSO + 2KI → K2SO + CuI2
(1)
(2)
(3)
4
4
2CuI2 → 2CuI + I2
I2 + I− ⇌ I3−
(1a) under the catalysis of CuI in THF, with no additional
assisting ligand, proceeded to completion in 90% yield of
5-iodotriazole 1 in 4 h (Scheme 3). Under these conditions,
Hein, Fokin, and co-workers reported no reaction starting with
other azides in the absence of an amine ligand such as triethyl-
amine (TEA) or TTTA.12 In our case, the chelating22 2-picolyl
azide and/or product 1 might act as “build-in” assisting ligands.
Cu(OAc)2, which mediates the CuAAC reactions involving
2-picolyl azide exceptionally well,22,23 showed a moderate reac-
tivity under otherwise identical conditions to afford 5-iodotriazole
1 in 41% after 2 days.
Under the same conditions, the reactions between several
other 1-iodoalkynes and 2-picolyl azide afforded 5-iodotriazoles
in moderate to good yields (55−84%, Table 1). The reactions
involving 4-(iodoethynyl)anisole (2a in entry 2, Table 1) and
3-iodo-N,N-dimethylpropargylamine (6a in entry 6, Table 1)
did not go to completion. No 5-iodotriazole product was
isolated using 4-iodoethynyl-N,N-dimethylaminobenzene (7a).
The three inefficient 1-iodoalkynes (2a, 6a, and 7a) are
relatively electron-rich and, hence, are weak iodinating agents in
trapping the copper(I) triazolide intermediate in the Cu/I
exchange step to afford 5-iodotriazole.12 The limited scope of
1-iodoalkyne substrates in conjunction with the occasional
difficulty in handling 1-iodoalkynes7 prompted us to explore
alternative methods to access 5-iodotriazoles starting from
stable terminal alkynes.
Inspired by this work, copper(II) perchlorate and sodium
iodide (NaI) were used to generate CuI and I2, in which CuI
catalyzes the cycloaddition of azide and alkyne, while I2 may
intercept the copper(I) triazolide intermediate to afford a
5-iodotriazole. In the presence of surplus I−, I3 forms (eq 3),
−
which is also an electrophilic iodinating agent, for instance, in
iodoform reactions. Reactions 1−3 complete within seconds
after mixing the reactants, which can be considered instantaneous.
The production of I2 and I3−, as well as the reduction of copper(II),
can be monitored conveniently using absorption spectroscopy
(Figure S1, Supporting Information).
In the 5-iodotriazole formation reactions described in this
paper, 2 molar equiv of copper(II) salt (0.4 mmol in the
captions of Tables 1−5) were used relative to the limiting agent
azide (0.2 mmol) because the molar ratio between copper(II)
−
and I2 (or I3 ) is 2:1 as shown in eqs 1−3, and 1 molar equiv of
−
I2 or I3 is needed for the formation of 5-iodotriazole. NaI
(4 molar equiv relative to the azide) was used, which ensures
−
that all of the formed I2 would be converted to I3 (eq 3), a
potent iodinating reagent. The reaction stoichiometry is later
depicted in the proposed mechanistic cycle (Scheme 4).
(b) Effect of a Base Additive. We selected 2-picolyl azide as
the organic azide component in the initial investigation of the
variables of the reaction conditions, because the self-
acceleratory effect of 2-picolyl azide significantly shortens the
conversion time. The scope of organic azides under the
optimized conditions is shown in Table 6 and is elaborated in
associated discussions.
Multicomponent Reaction To Generate 5-Iodotriazoles.
In the previously reported methods for preparing 5-iodo-
triazoles, a corrosive iodinating agent, such as ICl,8 or addi-
tional synthesis of unstable 1-iodoalkynes12 is required. Herein,
we report a simple and economical method for the selective
formation of 5-iodotriazoles starting from organic azide and
terminal alkyne, mediated by in situ generated copper(I)
The formation of 5-iodotriazole 1 from 2-picolyl azide and
phenylacetylene in THF in the presence of Cu(ClO4)2 and NaI
(Table 2, entry 1) was observed after 6 h in a low yield (19%).
B
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Scheme 3. Reaction of 2-Picolyl Azide with 1-Iodo-2-phenylethyne (1a) To Afford Compound 1
a
Table 1. “Ligand-Free”24 Synthesis of 5-Iodotriazoles Using 2-Picolyl Azide and 1-Iodoalkynes
a
b
Reaction conditions: 2-picolyl azide (0.4 mmol), 1-iodoalkyne (0.5 mmol), CuI (5 mol %), THF (2 mL), rt, 4 h. Reaction did not go to
c
completion. NR: no reaction.
With the addition of 1 equiv of triethylamine (TEA, entry 3),
the yield increased to 97%. Excessive inclusion of TEA led to
the formation of the undesired 5-proto-1,2,3-triazole (5-proto-
triazole in the following text) 1H (entry 4).28 No other side
products were observed in these reactions. At 1 molar equiv,
diethylamine (entry 5), DMAP (entry 7),29 and DBU (entry 8)
showed results comparable to those of TEA. The inorganic base
Na2CO3 showed selectivity for 1 over 1H with a moderate
conversion (68%, entry 9). Mixing Na2CO3 with 0.5 equiv
of TEA resulted in a complete conversion and selectivity for
5-iodotriazole 1 (entry 10).
It appears that an amine base is required for achieving a high
conversion. The excessive addition of the amine may lead to the
accumulation of its conjugated acid from deprotonating the
alkyne reactant. The conjugate acid ammonium ion as a
protonating agent competes with the iodinating reagent for the
copper(I) triazolide intermediate, thus compromising the iodo/
proto (1/1H in Table 2) selectivity. In addition to being a base,
the amine additive may act as a nucleophilic catalyst to activate
I2 to the more electrophilic iodinating reagent triethyliodoam-
monium ion, as suggested by Heaney et al.,30 and triiodide
(eq 4). The addition of TEA into an CH3CN solution of I2
−
results in the formation of I3 as observed in the absorption
spectra (Figure S2A, Supporting Information) and downfield
shifts of TEA hydrogen peaks in 1H NMR (Figure S2B,
Supporting Information), supporting the occurrence of the
reaction shown in eq 4.
+
Et3N + 2I2 ⇌ Et3N − I + I3−
(4)
(e) Solvent Effect. Various solvents were evaluated in the
reaction shown in Table 3 using TEA as the additive. The
selectivity for 5-iodotriazole over 5-prototriazole (iodo/proto
selectivity) was observed in all solvents. The reactions in
noncoordinating solvents (toluene and CH2Cl2, entries 1 and 3,
respectively)31 were sluggish. The ability of solvent to stabilize
copper(I) oxidation state affects the outcome of the reaction.
For example, copper(I) ion in water has a high propensity to
disproportionate,32 which likely contributed to the low isolated
C
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a
Table 2. Additive Effect on the Synthesis of 5-Iodotriazole 1
Table 4. Effect of Copper(II) Salt in the Formation of
a
5-Iodotriazole 1
b
entry
additive (pKa)
equiv
0.5
1/1H isolated yield of 1 (%)
d
b
1
2
none
1:0
3.5:1
1:0
19
68
97
84
91
79
96
90
68
96
entry
copper source
1/1H
isolated yield of 1 (%)
d
TEA (9.0)
TEA (9.0)
TEA (9.0)
Et2NH (9−10)
pyridine (3.4)
DMAP (9.2)
DBU (12)
1
2
3
4
5
Cu(ClO4)2
CuSO4
1:0
4.5:1
16:1
4:1
97
87
82
70
89
3
1.0
4
1.5
9:1
CuCl2
e
5
1.0
1:0
Cu(OAc)2
Cu(CF3SO3)2
CuI/I2
6
1.0
3.5:1
1:0
13:1
13:1
7
1.0
c
d
6
55
8
1.0
1:0
a
2-Picolyl azide (0.2 mmol), phenylacetylene (0.23 mmol), copper(II)
salt (0.4 mmol), NaI (0.8 mmol), TEA (0.2 mmol) THF (1 mL), rt,
f
d
9
Na2CO3 (10)
1.0
1:0
10
TEA/Na2CO3
0.5/5.0
1:0
b
c
1
6 h. Product ratio determined by H NMR. CuI (0.2 mmol), I2
(0.2 mmol). Reaction did not go to completion.
a
d
2-Picolyl azide (0.2 mmol), phenylacetylene (0.23 mmol), Cu(ClO4)2·
b
6H2O (0.4 mmol), NaI (0.8 mmol), THF (1 mL), rt, 6 h. pKa of the
conjugate acid in DMSO27 is shown in parentheses. Iodo/proto selec-
c
d
1
tivity: product ratio ([1]/[1H]) determined by H NMR. Reaction
(e) Scope of Terminal Alkyne. A number of terminal alkynes
were subjected to the optimized conditions, which include
Cu(ClO4)2 as the copper(II) source, TEA or DBU as the amine
additive, and THF or CH3CN as the solvent in reactions
with 2-picolyl azide (Table 5). The reactions proceeded to give
5-iodotriazole exclusively, with the exceptions of entries 2 and 4, in
which iodo/proto selectivities were 4:1 and 3:2, respectively.
Compound 6 (entry 4) was produced from N,N-dimethylpro-
pargylamine in 51% yield, which is comparable with that
afforded from the 1-iodoalkyne substrate (Table 1, entry 6).
The iodo/proto selectivity of entry 5 was not hindered by the
hydroxyl-containing alkyne substrate (propargyl alcohol),
indicating that the iodination outcompetes the protonation of
the copper(I) triazolide intermediate by an alcohol. Notably,
compound 9 (entry 7) was isolated in 84% yield, while the
related reaction using 1-iodoalkyne (Table 1, entry 7) failed
to occur. Using 2 equiv of 2-picolyl azide in the presence of
1,3-diethynylbenzene gave the bisiodotriazole compound 12
(entry 10), which is similar to a recently reported molecule
prepared via a 1-iodoalkyne intermediate.19 A comparable iso-
lated yield was achieved using the current method, which avoided
the synthesis of 1-iodoalkyne, and consequently shortened the
reaction time.
(f) X-ray Single-Crystal Structure of 5-Iodotriazole 1. Single
crystals of compound 1 suitable for X-ray diffraction were
obtained upon cooling a hot CD3CN solution of 1 to room
temperature (Figure 1). The dihedral angle between the planes
of 5-iodotriazolyl and phenyl moieties is 20.1°. The crystal
packing reveals several π−π interactions that vertically stack the
molecules. An intermolecular interaction between the pyridyl
nitrogen and the iodo substituent of an adjacent molecule was
observed (Figure 1), with a N1−I1 distance of 2.879 Å and an
N1−I1−C1 angle of 168.43°. This interaction can be classified
as “halogen bonding”, where a halogen atom on an electron-
deficient aromatic ring interacts with the lone pair electrons of
an electronegative atom in a similar manner to hydrogen bond-
ing.16 There is also a secondary interaction between the N2
nitrogen and the iodo-substituent (N2−I1: 3.800 Å), which
forces the pyridyl group slightly off the plane of the 5-iodo-
triazolyl, and the C2−N1−I1 angle (105°) from the expected
120°. To our knowledge, this is the first observation of
halogen bonding in the solid-state structures of 5-iodotriazoles
e
did not go to completion. Estimated to be 9−10. The value is not
listed in the Evans pKa table.27 pKa in water.
f
Table 3. Solvent Effect on the Formation of
5-Iodotriazole 1
a
b
entry
solvent
1/1H
isolated yield of 1 (%)
1
2
toluene
EtOAc
CH2Cl2
THF
2:1
1:0
1:0
1:0
1:0
1:0
1:0
13:1
1:0
2:1
58
74
c
3
44
4
97
90
93
86
5
acetone
CH3CN
DMF
6
7
c
8
2-propanol
methanol
water
40
c
9
68
c
10
23
a
2-Picolyl azide (0.2 mmol), phenylacetylene (0.23 mmol), Cu(ClO4)2·
6H2O (0.4 mmol), NaI (0.8 mmol), TEA (0.2 mmol), solvent (1 mL), rt,
b
c
6 h. Product ratio was determined by 1H NMR. Reaction did not go
to completion.
yield in water (entry 10). In acetone (entry 5) and CH3CN
(entry 6),33 copper(I) is stabilized. Consequently, high isolated
yields were achieved.
(d) Reactivity of Copper(II) Salt. Various copper(II) salts
were treated with NaI to convert to copper(I) with different
catalytic activities (Table 4). Copper(II) perchlorate34 and
copper(II) triflate (Table 4, entries 1 and 5), which contain
weakly coordinating anions, resulted in facile conversion and
excellent iodo/proto selectivity. The in situ generated copper(I)
catalyst and iodinating reagent were more reactive than the
pure forms of CuI and I2 (entry 6). The low reactivity of the
CuI/I2 combination in the syntheses of 5-iodotriazoles has also
been observed by others.8,9
D
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a
Table 5. 5-Iodotriazole Synthesis Applying Various Terminal Alkyne Molecules
a
2-Picolyl azide (0.2 mmol), alkyne (0.23 mmol), Cu(ClO4)2·6H2O (0.4 mmol), NaI (0.8 mmol), TEA (0.2 mmol), CH3CN (1 mL), rt, 6 h.
2-Picolyl azide (0.45 mmol), alkyne (0.2 mmol), TEA (0.4 mmol), Cu(ClO4)2·6H2O (0.8 mmol), NaI (1.6 mmol), CH3CN (1 mL), rt, 6 h.
b
(halogen bonding involving a 5-iodotriazolium in the solid state
the remaining azide reactant after 12 h. Presumably in these
cases, the 5-iodotriazole formation is slow enough to allow the
OHC reaction to be competitive. To mitigate the effect of
the alkyne OHC reaction, the amount of phenylacetylene was
doubled, which drove the reaction to completion in most
cases.37 The 5-iodotriazole was the sole product with few
exceptions. N-(2-Azidoethyl)pyrrolidine (entry 6, Table 6) gave
a significant amount of 5-prototriazole (∼ 30%). It was
described previously that an excess amount of TEA (Table 2,
entry 4) in the reaction leads to the formation of 5-proto-
triazole. In this case, a tertiary amino group is part of the azide
substrate.
was reported in ref 17).18,35
(g) Scope of Organic Azide. The scope of organic azide in
the formation of 5-iodotriazole was investigated in the reactions
with phenylacetylene (Table 6). In these reactions, DBU was
found to work more consistently than TEA to afford the
5-iodotriazole molecules. Benzyl azide (entry 1) and 3-trifluoro-
methylbenzyl azide12 (entry 2) showed high reactivity under
the developed conditions. Most other azides under the same
conditions led to the formation of a small amount of 5-iodo-
triazole product, 1,4-diphenylbuta-1,3-diyne, as the result of
alkyne oxidative homocoupling (OHC)36 and the recovery of
E
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nation of alkyne by a base, such as DBU or TEA, follows the
π-complex formation between the alkyne and copper(I)4 to
afford the copper(I) acetylide I. Similar to CuAAC reaction, the
acetylide formation step is rate-determining (or more precisely
“kinetically significant”, if other elementary steps also affect the
rate), because in the absence of a base the conversion is poor
(Table 2, entry 1). Subsequent azide coordination prompts the
formation of the dinuclear vinylidene-like intermediate III,
which undergoes a reductive ring contraction to reach the
−
copper(I) triazolide IV. An electrophilic iodinating reagent, I3
as shown in Scheme 4, captures the copper(I) triazolide to
afford 5-iodotriazole V. An excess amount of TEA (B) may con-
tribute to a high concentration of triethylammonium (B−H+ in
Scheme 4) upon alkyne deprotonation in the system, which
−
competes with I3 for copper(I) triazolide to afford the
byproduct 5-prototriazole (V′).
Figure 1. ORTEP view (30% ellipsoids) of compound 1.
Intermolecular interactions between 5-iodo group and N1/N2 on
the adjacent molecule are marked by dashed bonds.
From the proposed model, we conclude that the degree of
conversion of the reactants is determined by the reactivities of
the base (B) and the copper(I) catalyst, while the iodo/proto
selectivity depends on the relative strengths of iodinating reagents
and available protonating sources (i.e., B−H+). Therefore, both
conversion and selectivity are sensitive to the base: a high
concentration of base helps conversion but lowers the iodo/
proto selectivity. Under the current procedure, 1 molar equiv of
the base relative to the limiting reagent azide appears to be
optimal for both conversion and selectivity.
In addition to examples of aromatic (entry 3), benzylic
(entries 1, 2, 8, 10), and aliphatic azides (all other entries), a
number of common functional groups are represented in Table 6
(the inclusion of entries 9−12 was suggested by a reviewer).
Tertiary amino (entry 6) and ester (entry 9) groups were
tolerated. An isomer of 2-picolyl azide, 3-picolyl azide, pro-
ceeded to completion, albeit with a lower isolated yield (49%).
The inclusion of amide (entry 11) and carboxylic acid (entry 12)
groups in the azide structure resulted in no conversion, while
the azides were fully recovered. The addition of a catalytic
amount (10 mol %) of the known acceleratory ligand TBTA,
also suggested by a reviewer, led to full conversions of the
azides and respectable isolated yields in both cases after 6 h
(entries 11 and 12). A substantive investigation of acceleratory
ligand effect in 5-iodotriazole synthesis using the reported
method is currently underway.
(h) Reaction Mechanism. Under the developed conditions,
the reaction to form compound 1 was monitored via 1H NMR
in CD3CN. After the last component (alkyne) was added to the
reaction mixture, an aliquot of which was diluted with CD3CN
in an NMR tube to afford a homogeneous solution. The
1H NMR spectra of the reaction mixture were acquired at
prescribed intervals over time (Figure 2). The methylene
proton peaks are color-coded in Figure 2 to highlight the
change from 2-picolyl azide (blue) to 5-iodotriazole 1 (red).
Only the formation of compound 1 was observed without evi-
dence that the reaction proceeded through a 5-prototriazole
intermediate (i.e., 1H). Control experiments verified that 1H
could not be iodinated under the reaction conditions.
In an attempt to characterize the species formed from a
mixture of 2-picolyl azide, Cu(ClO4)2, and NaI in CH3CN,
tetrakis(acetonitrile)copper(I) perchlorate40 was isolated
(Figure S4, Supporting Information). The back-donation of
electrons from copper(I) to CH3CN protects copper(I) from
oxidation to copper(II).41 Ligand exchanges with CH3CN
would allow tetrakis(acetonitrile)copper(I) perchlorate to serve
as a precursor to other copper(I) complexes.42 The observation
of the tetrakis(acetonitrile)copper(I) perchlorate suggests that
under the reported in situ conditions, in addition to the freshly
formed CuI, other solvated or ligated copper(I) species may
also be present to catalyze the reaction, likely with a higher
activity than the pure form, coordinatively saturated CuI.
The observation of tetrakis(acetonitrile)copper(I) perchlo-
rate led us to investigate the nature of the formed I2. The
CH3CN solution of I2 shows three absorption bands at 294,
367 (shoulder), and 467 nm (blue trace in Figure 3).43−45
Addition of NaI to the I2 solution reduces the intensity of the
467 nm band and enhances those of the 294 and 367 nm bands
−
(red trace), thus reporting a shift of the equilibrium toward I3
(eq 3, also see Figure S1A, Supporting Information).44,46,47 The
absorption spectrum of the mixture of Cu(ClO4)2 and NaI in
1:2 molar ratio in CH3CN contains two bands at 294 and
367 nm with no appearance of a copper(II) d−d transition
band in the 700 nm range (green trace). The absence of the
The published mechanistic models of 5-iodotriazole forma-
tion from either terminal alkyne8 or 1-iodoalkyne12,30 share
much in common with that of the CuAAC reaction proposed
by Fokin, Sharpless, and co-workers.1,38 In one model that
invokes the formation of copper(I) acetylide,39 the elementary
steps track those of the CuAAC until the formation of copper(I)
triazolide, which is intercepted by an iodinating reagent such as
ICl,8 1-iodoalkyne,12 or triethyliodoammonium ion.30
−
467 nm band suggests that I2 exists in the form of I3 in the
reaction mixture.
An X-ray single-crystal structure of tetrabutylammonium
triiodide was obtained under conditions similar to those applied
in the reported reactions. Mixing copper(II) perchlorate with
Bu4NI, which is capable of replacing NaI in the reaction
depicted in Table 2, entry 3, to afford compound 1, in CH3OH
gave CuI as an off-white precipitate that was filtered off. Slow
evaporation of the filtrate led to the formation of dark red
single crystals, which were solved to be tetrabutylammonium
triiodide48 (Figure 4).
The mechanistic model that accounts for our observations is
depicted in Scheme 4. Under the reported conditions, the
copper(II) salt reacts with NaI to give copper(I) species, I2, and
−
I3 , when NaI exceeds 1 molar equiv relative to copper(II).
−
Both the copper(II) reduction and I3 formation steps can be
monitored using absorption spectroscopy and are considered
instantaneous (Figure S1, Supporting Information). Deproto-
F
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a
Table 6. 5-Iodotriazole Synthesis Applying Various Organic Azides
a
Azide (0.2 mmol), phenylacetylene (0.23 mmol), Cu(ClO4)2·6H2O (0.4 mmol), NaI (0.8 mmol), DBU (0.2 mmol), THF or CH3CN (1 mL), rt,
b
c
d
12 h. Same as condition (a) except the amount of phenylacetylene (0.5 mmol). Reaction did not go to completion. A catalytic amount of N,N,N-
tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA, 0.02 mmol) was added. Reaction time: 6 h. No conversion was observed in the absence of
TBTA.
−
−
The use of I3 as an iodinating reagent in the iodination of
triazolide intermediate. To assess the relative reactivities of I3
acetone is well-known.49,50 It is probable in the present case
that I3 is more reactive than I2 in iodinating the copper(I)
and I2, two reactions were investigated involving 2-picolyl azide,
phenylacetylene, CuI (0.5 equiv), and DBU in CH3CN, where
−
G
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−
when Bu4NI3 was used. It is unclear why I3 led to a better
conversion than I2. Our current hypothesis, which needs to be
Scheme 4. Mechanistic Model of the One-Pot Conditions To
Generate 5-Iodotriazole
a
−
tested in the near future, is that I3 may interact with CuI to
form a more potent catalyst.
The reactions to afford 5-iodotriazole 1 under the optimized
conditions with different concentrations of NaI were followed
51
1
by H NMR (Figure 5A). The initial rates were determined,
by which the apparent kinetic order of NaI was estimated to be
4.4 (Figure 5B). The abnormally high kinetic order of NaI is
−
consistent with the kinetic significance of I3 . The poor linearity
of the correlation perhaps is a manifestation of the varying
distribution of I−, I2, and I3− at different NaI concentrations. A
complete kinetic investigation will be carried out to determine
the kinetic involvements of other components in the reaction.
(i). One-Pot Synthesis of 5-Allyl-1,4-disubstituted-1,2,3-
triazole 25. On the basis of the mechanistic picture in Scheme
−
4, an electrophile other than I3 shall also trap the copper(I)
triazolide intermediate IV to complete the C5-functionalization.
To test this hypothesis, the loadings of Cu(ClO4)2 and NaI
were reduced, while the electrophilic allyl iodide was
introduced to the reaction mixture of 2-picolyl azide and
1-hexyne. The formation of 2-((5-allyl-4-butyl-1,2,3-triazol-1-yl)-
methyl)pyridine (25) was observed at 15 mol % Cu(ClO4)2
loading in CH3CN. The reaction did not reach completion after
12 h and showed a mixture of the 5-iodotriazole product (1)
and 25. Increasing the Cu(ClO4)2 loading to 0.5 equiv improved
the conversion but also promoted the formation of 1. In the
Kauffman and Pinnell synthesis of CuI from copper(II) salts
and NaI, I2 was eliminated by sodium thiosulfate.26 The addi-
tion of sodium thiosulfate to the reaction mixture containing
a
Key: blue, copper(II); orange, copper(I); green, copper(III). B: base,
−
i.e., TEA. We note that in addition to I3 , other iodinating species,
such as triethyliodoammonium, may also participate in the reaction.
one contained Bu4NI3 and the other I2. The reaction with I2 did
not complete after 20 h (29% 2-picolyl azide remains as
determined by H NMR) and showed a mixture of 1 and 1H
(68% and 3%, respectively). The reaction involving Bu4NI3
reached completion exclusively to 1. These results suggest that
I3 is a better electrophile than I2 under the reported
conditions, based on the improved iodo/proto selectivity
1
−
Figure 2. 1H NMR (500 MHz, CD3CN) spectra of 2-picolyl azide (5.2 mM) with phenylacetylene (9.4 mM) in the presence of Cu(ClO4)2·6H2O
(10 mM), NaI (21 mM), and TEA (5.7 mM), taken at every 50 min. The methylene proton peaks of 2-picolyl azide and iodotriazole 1 are marked
blue and red, respectively.
H
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Scheme 5. One-Pot, Multicomponent Synthesis of 5-Allyl-
a
1,2,3-triazole 25
a
Key: 2-picolyl azide (0.20 mmol), NaI (0.20 mmol), Na2S2O3 (1.0
mmol), Cu(ClO4)2·6H2O (0.10 mmol), DBU (0.20 mmol), allyl iodide
(0.33 mmol), and 1-hexyne (0.23 mmol) in THF (1 mL), rt, 12 h.
give an isolated yield of compound 25 at 76%.52 5-Allylation by
trapping the copper(I) triazolide have been reported by others
under CuI- or CuBr-mediated, but otherwise similar, conditions.8,10
Notable improvements in the current work include the reduced use
of allyl iodide and the copper (pre)catalyst, relatively short reac-
tion time, and tolerance of air exposure, compared to the existing
methods.
Figure 3. Absorption spectra of solutions of I2 (1.1 mM, blue), mixture
of I2 (38 μM) and NaI (38 μM, red), and reaction mixture of
Cu(ClO4)2 (40 μM) and NaI (80 μM, green) in CH3CN.
CONCLUSION
■
In summary, we have shown that 5-iodo-1,4-disubstituted-1,2,3-
triazoles can be prepared from the CuI-mediated cycloaddi-
tion reaction of 2-picolyl azide and 1-iodoalkynes without the
addition of an assisting ligand. To circumvent the synthesis of
1-iodoalkynes, a one-pot, multicomponent procedure has been
developed where a copper(II) salt is reduced by NaI to generate in
situ the copper(I) catalyst and the iodinating source, I3−. The in
situ generated copper(I) catalyst and I3− are more reactive than
the pure forms of CuI and I2, respectively, likely because (1) the in
situ copper(I) species is better solvated and hence undergoes
more efficient ligand exchange than the pure form of CuI and (2)
I3− ion is a stronger electrophilic iodinating agent than I2. The
reaction also requires 1 equiv of an amine additive, which may act
as a nucleophilic catalyst to deliver the iodinating reagents, in
addition to deprotonating the alkyne substrate. The resulting
conjugate acid is considered to be an efficient proton donor,
which, at a relatively high concentration, protonates copper(I)
triazolide to compete with iodination. Extending from this work,
more systematic mechanistic investigations are planned to
elucidate the functions of various components, including
accelerating ligands, in determining the conversion and iodo/
proto selectivity of the reaction, based on which the conditions for
C5 functionalization can be optimized, and the scope be expanded.
Figure 4. ORTEP view (30% ellipsoids) of tetrabutylammonium
triiodide. Carbon atoms are shown in black, nitrogen in blue, and
iodine in purple.
0.5 equiv of Cu(ClO4)2 drove the reaction to completion in
12 h (Scheme 5). 5-Iodotriazole 1 still formed as a minor
component, which can be separated chromatographically to
Figure 5. (A) Time courses of compound 1 formation at various ratios of [Cu(ClO4)2]/[NaI] shown in the legend. Conditions: [2-picolyl azide] =
15 mM; [phenylacetylene] = 17 mM; [TEA] = 15 mM; [Cu(ClO4)2] = 30 mM. (B) Plot of ln V (initial rate) vs ln[NaI]. The slope yields the kinetic
order of NaI.
I
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(300 MHz, CDCl3) δ/ppm: 8.00 (bs, 1H), 7.55 (d, J = 7.8 Hz, 2H),
7.36 (t, J = 7.8 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 4.16 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ/ppm: 164.8, 136.9, 129.3, 125.2, 120.3, 53.1.
MS (EI) (m/z): [M]+ calcd for C8H8ON4 176.0698, found 176.0686.
Synthesis of 3-Picolyl Azide. 3-Picolyl chloride hydrogen
chloride (430 mg, 3.0 mmol) and NaN3 (846 mg, 12.9 mmol) were
mixed in CH3CN (15 mL) in a round-bottom flask equipped with a
magnetic stirring bar. DIPEA (390 mg, 3.0 mmol) and catalytic
amounts of 18-crown-6 and Bu4NI were added sequentially. The
reaction mixture was stirred at rt for 19 h before ethyl acetate (90 mL)
was added. The white precipitate was filtered off, and the solution was
washed with basic brine (pH = 11). The organic layer was dried over
Na2SO4. 3-Picolyl azide (109 mg, 81%) was obtained after solvent
EXPERIMENTAL SECTION
■
Materials and General Methods. Warning! Low molecular
weight organic azides and copper(II) perchlorate used in this study
are potentially explosive. Appropriate protective measures should
always be taken when handling these compounds. Reagents and
solvents were purchased from various commercial sources and used
without further purification unless otherwise stated. Analytical thin-
layer chromatography (TLC) was performed using precoated TLC
plates with silica gel 60 F254 or with aluminum oxide 60 F254 neutral.
Flash column chromatography was performed using 40−63 μm (230−
400 mesh ASTM) silica gel or alumina (80−200 mesh, pH 9−10) as
the stationary phases. Silica and alumina gel were flame-dried under
vacuum to remove adsorbed moisture before use. H and 13C NMR
1
1
removal. H NMR (300 MHz, CDCl3) δ/ppm: 8.59 (s, 2H), 7.68
spectra were recorded at 500 (or 300) and 125 (or 75) MHz,
respectively, at 295 K unless otherwise noted. The chemical shifts (δ)
are recorded in ppm relative to the residual CHCl3 or CHD2CN as
internal standards. Synthesis of 1-iodoalkynes followed a previously
reported procedure.21 All 1-iodoalkynes synthesized in this work were
previously reported: 1-(iodoethynyl)benzene,53,54 4-(iodoethynyl)-
anisole,54,55 2-(iodoethynyl)pyridine,54 1-iodohexyne,56 3-iodo-N,N-
dimethylpropargylamine,12 and [(3-iodo-2-propynyl)oxy]benzene.57
“Assisting Ligand-Free” Conditions To Prepare 5-Iodotria-
zoles. A freshly prepared solution of 1-iodo-2-phenylethyne (114 mg,
0.50 mmol) in THF (2 mL) was mixed with 2-picolyl azide (0.40 mmol,
54 mg). A catalytic amount of CuI (<2 mg) was added, and the
reaction mixture was stirred at rt for 4 h. Following completion, the
mixture was loaded on a short silica column using CH2Cl2. The
column was eluted with CH2Cl2 containing an increasing amount of
ethyl acetate up to 50% v/v to yield the pure compound.
(d, J = 7.8 Hz, 1H), 7.36−7.32 (m, 1H), 4.40 (s, 2H). 13C NMR
(125 MHz, CDCl3) δ/ppm: 149.6, 149.2, 135.7, 131.1, 123.6, 52.0.
Representative Procedure for the One-Pot Synthesis of
5-Iodotriazole. 2-Picolyl azide (27 mg, 0.20 mmol) was dissolved in
THF (1 mL, comparable yields were obtained in CH3CN) in a 10-mL
round-bottom flask equipped with a magnetic stirring bar. To this
solution were added NaI (120 mg, 0.80 mmol) and Cu(ClO4)2·6H2O
(148 mg, 0.40 mmol). The reaction was stirred for ∼3−5 min before
DBU (30 μL, 0.20 mmol) and phenylacetylene (25 μL, 0.23 mmol)
were added. The stirring continued at rt for 6 h before the reaction
mixture was diluted with ethyl acetate (50 mL) and washed
sequentially with a 28−30% w/w NH4OH solution (25 mL) and
brine (2 × 25 mL). The organic layer was separated and dried over
Na2SO4. The solvent was removed under reduced pressure to afford
the crude product as a light yellow powder, which was purified on a
silica column eluted with CH2Cl2 with an increasing amount of ethyl
acetate up to 50% v/v as a white powder in 97% yield (70 mg).
For other azides, up to 0.5 mmol of alkyne may be needed for the limit
reagent azide (0.2 mmol) to fully convert. The completion of a reaction,
which may take less than 6 h, usually is associated with the complete
fading of the dark brown color of the initial reaction mixture. For the
syntheses of compounds 23 and 24, a catalytic amount of TBTA (0.02
mmol) was added before the addition of DBU and phenylacetylene.
Compound 1. Isolated as an off-white solid in 97% yield (70 mg).
Synthesis of n-Butyl Azidoacetate. n-Butanol (741 mg, 10 mmol)
was dissolved in toluene (15 mL) in a round-bottom flask equipped
with a magnetic stir bar. The flask was seated in a water bath at rt
before chloroacetyl chloride (1.13 g, 10 mmol) and diisopropylethyl-
amine (1 mL) were added dropwise sequentially. After the addition,
the reaction mixture was stirred at rt for 3 h. The reaction mixture was
then diluted with CH2Cl2 (50 mL) and washed with deionized water
(3 × 50 mL) and brine (50 mL) sequentially. The organic layer was
separated and dried over Na2SO4. Upon solvent removal, n-butyl
chloroacetate was dissolved in CH3CN (20 mL). NaN3 (3.25 g,
50 mmol) was subsequently added along with catalytic amounts of
18-crown-6 and Bu4NI. The reaction mixture was stirred at rt for 48 h
before CH3CN was removed under reduced pressure using a rotatory
evaporator. The residue was diluted in CH2Cl2, which was washed
with brine (3 × 50 mL) in a separation funnel. The organic layer was
separated and dried over Na2SO4. Upon solvent removal,
the residue was eluted through a short silica column using CH2Cl2
(100 mL). n-Butyl azidoacetate (1.40 g) was isolated upon solvent
1
Mp: 150−152 °C. H NMR (500 MHz, CD3CN): δ/ppm 8.52 (ddd,
J = 4.8, 1.7, 0.9 Hz, 1H), 7.95−7.91 (m, 2H), 7.77 (td, J = 7.7, 1.8 Hz,
1H), 7.54−7.48 (m, 2H), 7.44 (tt, J = 7.4, 1.6 Hz, 1H), 7.33−7.29
(m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 5.80 (s, 2H). 13C NMR (125 MHz,
CD3CN, 323 K) δ/ppm 155.8, 151.1, 150.8, 138.4, 132.1, 129.8, 129.8,
128.6, 124.4, 123.1, 79.8, 56.7. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C14H12N4I 363.0107, found 363.0116.
Compound 2. Isolated as an off-white solid in 83% yield (65 mg).
1
Mp: 98−106 °C. H NMR (500 MHz, CD3CN, 333 K): δ/ppm 8.53
1
(d, J = 4.4 Hz, 1H), 7.87 (dt, J = 9.0, 2.5 Hz, 2H), 7.75 (td, J = 7.7,
1.8 Hz, 1 H), 7.29 (dd, J = 7.6, 4.9 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H),
7.05 (dt, J = 8.9, 2.6 Hz, 2H), 5.77 (s, 2H), 3.85 (s, 3H). 13C NMR
(125 MHz, CD3CN, 333 K) δ/ppm 161.5, 156.0, 151.1, 150.8, 138.4,
130.1, 124.6, 124.4, 123.2, 115.4, 78.9, 56.8, 56.4. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C15H14N4IO 393.0212, found 393.0219.
Compound 3. Isolated as a light yellow solid in 74% yield (54 mg).
Mp: 145−147 °C. 1H NMR (500 MHz, CD3CN): δ/ppm 8.66
(bs, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.11 (bs, 1H), 7.87 (t, J = 7.6 Hz,
1H), 7.76 (td, J = 7.7, 1.9 Hz, 1H), 7.35 (bs, 1H), 7.32−7.27 (m, 1H),
7.18 (d, J = 7.9 Hz, 1H), 5.83 (s, 2H). 13C NMR (125 MHz, CD3CN,
323 K) δ/ppm 155.8, 151.3, 150.8, 150.1, 149.6, 138.3, 138.0, 124.4,
124.3, 123.0, 122.7, 80.5, 56.5. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C13H11N5I 364.0059, found 364.0065.
removal in 89% yield over two steps. H NMR (300 MHz, CDCl3)
δ/ppm: 4.22 (t, J = 6.0 Hz, 2H), 3.83 (s, 2H), 1.64 (pent, J = 6.0 Hz,
2H), 1.40 (sext, J = 6.0 Hz, 2H), 0.95 (t, J = 6.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ/ppm: 168.5, 65.7, 50.3, 30.5, 19.0, 13.6. MS
(EI) (m/z): [M]+ calcd for C6H11N3O2 157.0851, found 157.0839.
Synthesis of 2-Azido-N-phenylacetamide. Aniline (931 mg,
10 mmol) was dissolved in toluene (15 mL) in a round-bottom flask
equipped with a magnetic stirring bar. Chloroacetyl chloride (1.13 g,
10 mmol) and diisopropylethylamine (1 mL) were added dropwise
sequentially. After the addition, the reaction mixture was stirred at rt
for 2 h. Subsequently, the reaction mixture was diluted with CH2Cl2
(50 mL) and washed with deionized water (3 × 50 mL) and brine
(50 mL) sequentially. The organic layer was separated and dried over
Na2SO4. Upon solvent removal, the recovered 2-chloro-N-phenyl-
acetamide was mixed with NaN3 (3.25 g, 50 mmol) in CH3CN
(20 mL) in a round-bottom flask with a stirring bar. Catalytic amounts
of 18-crown-6 and Bu4NI were added, and the mixture was stirred at rt
for 45 h. The reaction was then diluted with CH2Cl2 (70 mL),
transferred to a separation funnel, and washed with brine (3 × 50 mL).
The organic layer was dried over Na2SO4. Upon solvent removal, the
residue was eluted using CH2Cl2 (100 mL) through a short silica
Compound 4. Isolated as a yellow oil in 97% yield (66 mg).
1H NMR (500 MHz, CD3CN, 323 K): δ/ppm 8.52 (d, J = 3.8 Hz,
1H), 7.73 (td, J = 7.7, 1.8 Hz, 1H), 7.28 (dd, J = 5.0, 7.6 Hz, 1H), 7.07
(d, J = 7.9 Hz, 1H), 5.68 (s, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.71−1.63
(m, 2H), 1.43−1.34 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR
(125 MHz, CD3CN, 323 K) δ/ppm 155.0, 153.2, 150.7, 138.2, 124.2,
122.9, 80.9, 56.4, 32.0, 26.7, 23.0, 14.2. HRMS (ESI-TOF) (m/z):
[M + H]+ calcd for C12H16N4I 343.0420, found 343.0410.
1
column to afford 2-azido-N-phenylacetamide (1.58 g, 90%). H NMR
J
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Compound 5. Isolated as a beige solid in 73% yield (117 mg). Mp:
94−96 °C. 1H NMR (500 MHz, CDCl3): δ/ppm 8.59 (d, J = 4.8 Hz,
1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.33−7.27 (m, 2H), 7.24 (dd,
J = 7.8, 5.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H),
6.93 (d, J = 7.9 Hz, 1H), 5.76 (s, 2H), 5.16 (s, 2H). 13C NMR (125
MHz, CDCl3) δ/ppm 158.4, 154.1, 149.8, 148.1, 137.4, 129.6, 123.4,
121.7, 121.5, 115.2, 81.7, 61.9, 55.8. HRMS (EI+) (m/z): [M]+ calcd
for C15H13N4IO 392.0134, found 392.0124.
Compound 14.12 Isolated as a white solid at 93% yield (80 mg).
1H NMR (300 MHz, CD3CN): δ/ppm 7.96−7.88 (m, 2H), 7.70−7.40
(m, 7H), 5.77 (s, 2H).
Compound 15. Isolated as a white solid in 70% yield (52 mg). Mp:
208−210 °C. 1H NMR (500 MHz, CDCl3, 323 K): δ/ppm 8.06−8.00
(m, 2H), 7.53−7.40 (m, 5H), 7.08 (dt, J = 8.9, 2.9 Hz, 2H), 3.92
(s, 3H). 13C NMR (125 MHz, CDCl3, 328 K) δ/ppm 161.3, 150.4,
130.7, 130.5, 128.9, 128.8, 128.2, 128.0, 114.8, 78.4, 55.9. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C15H13N3IO 378.0103, found
378.0114.
1
Compound 6. Isolated as a pale yellow gum in 55% (76 mg). H
NMR (500 MHz, CDCl3): δ/ppm 8.56 (d, J = 4.8 Hz, 1H), 7.62 (td,
J = 7.8, 1.8 Hz, 1H), 7.21 (dd, J = 7.2, 5.0 Hz, 1H), 6.85 (d, J = 7.9 Hz,
1H), 5.74 (s, 2H), 3.55 (s, 2H), 2.29 (s, 6H). 13C NMR (125 MHz,
CDCl3) δ/ppm 154.4, 149.7, 148.9, 137.2, 123.2, 121.4, 81.9, 55.6,
54.0, 45.2. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C11H15N5I
344.0372, found 344.0372.
Compound 7. Isolated as a white powder in 78% yield (49 mg).
Mp: 114−120 °C. 1H NMR (500 MHz, CD3CN, 323 K): δ/ppm 8.52
(d, J = 4.6 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.30 (dd, J = 7.7, 5.0
Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 5.71 (s, 2H), 4.60 (s, 2H). 13C
NMR (125 MHz, CD3CN, 323 K) δ/ppm 155.8, 152.5, 150.7, 138.3,
124.4, 123.1, 81.9, 57.0, 56.4. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C9H10N4IO 316.9899, found 316.9904.
Compound 16.8 Isolated as a light yellow solid in 98% yield
(77 mg). 1H NMR (500 MHz, CD3CN): δ/ppm 7.92−7.87 (m, 2H),
7.53−7.46 (m, 2H), 7.45−7.40 (m, 1H), 4.44 (t, J = 7.2 Hz, 2H),
1.96−1.86 (m, 2H), 1.40−1.22 (m, 10H), 4.44 (t, J = 7.2 Hz, 3H).
Compound 17. Isolated as a white powder in 58% yield (46 mg).
1
Mp: 137−142 °C. H NMR (500 MHz, CD3CN): δ/ppm 7.91−7.87
(m, 2H), 7.52−7.47 (m, 2H), 7.42 (tt, J = 7.4, 1.5 Hz, 1H), 7.30−7.24
(m, 2H), 6.95 (tt, J = 7.4, 1.0 Hz, 1H), 6.91−6.87 (m, 2H), 4.83 (t, J =
5.3 Hz, 2H), 4.50 (t, J = 5.3 Hz, 2H). 13C NMR (125 MHz, CD3CN,
323 K) δ/ppm 159.4, 150.7, 132.0, 130.7, 129.8, 129.7, 128.7, 122.5,
115.9, 80.0, 67.4, 51.3. HRMS (EI+) (m/z): [M]+ calcd for
C16H14N3IO 391.0182, found 391.0174.
Compound 18. Isolated as a light brown solid in 65% yield
Compound 8. Isolated as a white solid in 88% yield (60 mg). Mp:
1
(48 mg). Mp: 132−133 °C. H NMR (500 MHz, CD3CN): δ/ppm
1
117−118 °C. H NMR (500 MHz, CD3CN, 323 K): δ/ppm 8.52
7.92−7.88 (m, 2H), 7.52−7.47 (m, 2H), 7.43 (tt, J = 7.4, 1.7 Hz, 1H),
4.55 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.58−2.53 (m, 4H),
1.74−1.69 (m, 4H). 13C NMR (125 MHz, CD3CN, 323 K) δ/ppm
150.5, 132.2, 129.8, 129.7, 128.6, 79.1, 56.1, 55.0, 51.2, 24.7. HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C14H18N4I 369.0576, found
369.0573.
(d, J = 4.6 Hz, 1H), 7.73 (td, J = 7.7, 1.8 Hz, 1H), 7.28 (dd, J = 7.6, 5.0
Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.70 (s, 2H), 1.47 (s, 9H). 13C
NMR (125 MHz, CD3CN, 323 K) δ/ppm 158.1, 156.2, 150.7, 138.3,
124.2, 122.9, 76.7, 56.5, 32.7, 30.2. HRMS (ESI-TOF) (m/z): [M +
H]+ calcd for C12H16N4I 343.0420, found 343.0417.
Compound 9. Isolated as a dark solid in 84% (68 mg). Mp: 143−
Compound 20. Isolated from a short silica column eluted by
CH2Cl2 containing an increasing amount of ethyl acetate up to 100%
v/v as an off-white solid in 69% yield (89 mg). Mp: 215−216 °C.
1H NMR (500 MHz, DMSO-d6, 333 K): δ/ppm 7.90−7.82 (m, 5H),
7.50−7.35 (m, 6H), 7.19 (d, J = 7.7 Hz, 2H), 5.79 (s, 4H). 13C NMR
(125 MHz, DMSO-d6, 333 K) δ/ppm 154.2, 148.5, 138.0, 130.4,
128.1, 127.8, 126.7, 120.7, 81.4, 54.4. HRMS (EI+) (m/z): [M]+ calcd
for C23H17N7I2 644.9635, found 644.9630.
1
145 °C. H NMR (500 MHz, CDCl3): δ/ppm 8.61 (d, J = 3.8 Hz,
1H), 7.88 (dt, J = 9.0, 2.5 Hz, 2H), 7.65 (td, J = 7.3, 1.7 Hz, 1H), 7.24
(dd, J = 7.1, 5.2 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.80 (dt, J = 8.9, 2.4
Hz, 2H), 5.81 (s, 2H), 3.01 (s, 6H). 13C NMR (125 MHz, CDCl3) δ/
ppm 154.8, 150.8, 150.7, 149.8, 137.4, 128.4, 123.2, 121.6, 118.2,
112.2, 75.8, 55.9, 40.6. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C16H17N5I 406.0529, found 406.0517.
Compound 21. Isolated as an off-white amorphous solid in 95%
yield (73 mg). 1H NMR (300 MHz, CDCl3) δ/ppm: 7.96 (dd, J = 1.2,
3.6 Hz, 2H), 7.51−7.41 (m, 3H), 5.27 (s, 2H), 4.24 (t, J = 6.6 Hz,
2H), 1.64 (pent, J = 7.2 Hz, 2H), 1.36 (sext, J = 7.8 Hz, 2H), 0.92
(t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ/ppm: 165.8,
150.3, 130.1, 128.8, 127.6, 78.0, 66.5, 51.8, 30.5, 19.1, 13.8. HRMS
(ESI+) (m/z): [M + H]+ calcd for C14H17N3IO2 386.0365, found
386.0359.
Compound 10. Isolated as a light yellow solid in 93% yield
1
(76 mg). Mp: 174−175 °C. H NMR (300 MHz, CDCl3) δ/ppm:
8.62 (d, J = 4.2 Hz, 1H), 8.33 (d, J = 9.0 Hz, 2H), 8.23 (d, J = 9.0 Hz,
2H), 7.71 (dt, J = 1.8, 7.8 Hz, 1H), 7.31−7.26 (m, 1H), 7.06 (d, J = 7.8
1
Hz, 1H). H NMR (500 MHz, CD3CN): δ/ppm 8.53 (d, J = 4.5 Hz,
1H), 8.33 (dt, J = 9.1, 2.3 Hz, 2H), 8.25 (dt, J = 9.1, 2.2 Hz, 2H), 7.78
(td, J = 7.7, 1.8 Hz, 1H), 7.32 (dd, J = 7.4, 5.2 Hz, 1H), 7.24 (d, J = 7.9
Hz, 1H), 5.83 (s, 2H). 13C NMR (125 MHz, CD3CN, 323 K) δ/ppm
155.7, 151.0, 149.3, 149.2, 138.5, 138.5, 129.3, 125.2, 124.6,
123.4, 81.4, 57.0. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C14H11N5IO2 407.9957, found 407.9954.
Compound 11. Isolated as a white powder in 75% yield (54 mg).
Mp: 136−137 °C. 1H NMR (500 MHz, CD3CN): δ/ppm 9.14
(s, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.27 (ddd,
J = 7.9, 2.4, 1.6 Hz, 1H), 7.78 (td, J = 7.7, 1.8 Hz, 1H), 7.45 (ddd, J =
8.0, 4.9, 0.7 Hz, 1H) 7.33−7.29 (m, 1H), 7.22 (d, J = 7.9 Hz, 1H), 5.81
(s, 2H). 13C NMR (125 MHz, CD3CN, 323 K) δ/ppm 155.4, 150.6,
150.5, 149.1, 148.4, 138.2, 135.5, 127.8, 124.6, 124.3, 123.0, 80.9, 56.5.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C13H11N5I 364.0059,
found 364.0056.
Compound 22. Isolated as an off-white amorphous solid in 49%
1
yield (35 mg). H NMR (300 MHz, CDCl3) δ/ppm: 8.71 (s, 1H),
8.61 (d, J = 3.9 Hz, 1H), 7.92 (d, J = 6.9 Hz, 2H), 7.64 (d, J = 8.1 Hz,
1H), 7.47−7.38 (m, 3H), 7.32−7.30 (m, 1H), 5.70 (s, 2H). 13C NMR
(125 MHz, CDCl3) δ/ppm: 150.5, 150.1, 149.4, 135.8, 130.3, 130.1,
128.9, 128.7, 127.5, 124.1, 52.0. HRMS (ESI+) (m/z): [M + H]+ calcd
for C14H12N4I 363.0107, found 363.0107.
Compound 23. Isolated as an off-white amorphous solid in 80%
1
yield (65 mg). H NMR (300 MHz, CDCl3) δ/ppm: 7.97 (d, J =
7.2 Hz, 2H), 7.60 (bs, 1H), 7.51−7.46 (m, 5H), 7.34 (t, J = 7.8 Hz,
1
2H), 7.18 (t, J = 7.8 Hz, 1H), 5.34 (s, 2H). H NMR (500 MHz,
DMSO-d6) δ/ppm: 10.6 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.63 (d, J =
8.6 Hz, 2H), 7.54 (t, J = 7.9 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.36
(t, J = 8.4 Hz, 2H), 7.11 (t, J = 7.4 Hz, 1H), 5.47 (s, 2H). 13C NMR
(125 MHz, DMSO-d6) δ/ppm: 163.6, 148.6, 138.4, 130.6, 129.0,
128.8, 128.4, 126.8, 123.9, 119.3, 83.0, 53.2. HRMS (ESI+) (m/z):
[M + H]+ calcd for C16H14N4IO 405.0212, found 405.0198.
Compound 12. Isolated as an off-white solid in 53% (68 mg). Mp:
175−178 °C. 1H NMR (300 MHz, CDCl3) δ/ppm: 8.62 (d, J =
1.8 Hz, 2H), 8.04 (dd, J = 1.8, 7.8 Hz, 2H), 7.69 (dt, J = 1.8, 7.8 Hz,
2H), 7.59 (t, J = 7.8 Hz, 1H), 7.28−7.24 (m, 2H), 6.98 (d, J = 8.4 Hz,
2H), 5.86 (s, 4H). 13C NMR (125 MHz, CD3CN, 333 K) δ/ppm
155.9, 150.9, 150.8, 138.4, 132.6, 130.4, 128.7, 127.2, 124.4,
123.2, 80.0, 56.9. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C22H16N8I2Na 668.9480, found 668.9473.
Compound 24. The crude product after extraction was triturated
with diethyl ether (3 × 10 mL) to afford an off-white amorphous solid
in 62% yield (43 mg). The solubility of 24 is too low in the solvents
that we use to allow for the acquisition of a satisfactory 13C NMR
Compound 13.8 Isolated as a white solid in 93% yield (67 mg). 1H
NMR (500 MHz, CD3CN): δ/ppm 7.95−7.85 (m, 2H), 7.55−7.46
(m, 2H), 7.46−7.31 (m, 4H), 7.30−7.25 (m, 2H), 5.70 (s, 2H).
1
spectrum. Therefore, only H NMR and HRMS data are reported.
1H NMR (500 MHz, CD3OD) δ/ppm: 7.85 (d, J = 8.2 Hz, 2H), 7.48
(t, J = 7.4 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), 4.72 (t, J = 7.0 Hz, 2H),
K
dx.doi.org/10.1021/jo300841c | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
3.07 (t, J = 7.0 Hz, 2H). HRMS (ESI+) (m/z): [M + H]+ calcd for
C11H11N3IO2 343.9896, found 343.9907.
(12) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin,
V. V. Angew. Chem., Int. Ed. 2009, 48, 8018−8021.
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2011, 44, 4735−4741.
Procedure for the One-Pot Synthesis of Compound 25. 2-
Picolyl azide (27 mg, 0.20 mmol) was dissolved in THF (1 mL). To
this solution were added NaI (30 mg, 0.20 mmol), Na2S2O3 (158 mg,
1.0 mmol), and Cu(ClO4)2·6H2O (37 mg, 0.10 mmol). The reaction
mixture was stirred for ∼5 min before DBU (30 μL, 0.20 mmol), allyl
iodide (30 μL, 0.33 mmol), and 1-hexyne (26 μL, 0.23 mmol) were
added. The stirring was continued at rt for 12 h. Upon completion, the
reaction mixture was eluted through a short silica column using
CH2Cl2 to remove inorganic materials. Solvent removal followed by
purification on a silica column eluted with CH2Cl2 containing an
increasing amount of ethyl acetate up to 50% v/v afforded a pale
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yellow oil in 76% yield (39 mg). H NMR (500 MHz, CD3CN):
2011, 13, 3494−3497.
δ/ppm 8.50 (d, J = 4.3 Hz, 1H), 7.73 (td, J = 7.8, 1.8 Hz, 1H), 7.28
(dd, J = 7.8, 5.1 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 5.75−5.65 (m, 1H),
5.2 (s, 2H), 4.97 (dq, J = 10.2, 1.6 Hz, 1H), 4.86 (dq, J = 17.2, 1.6 Hz,
1H), 3.39 (dt, J = 6.0, 1.7 Hz, 2H) 2.57 (t, J = 7.6 Hz, 2H), 1.60−1.52
(m, 2H), 1.36−1.27 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (125
MHz, CD3CN) δ/ppm 156.1, 150.6, 146.6, 138.4, 134.2, 132.4, 124.2,
123.2, 117.4, 53.8, 32.6, 27.2, 25.3, 23.1, 14.2. HRMS (EI+) (m/z):
[M]+ calcd for C15H20N4 257.1766, found 257.1763.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(24) Presumably, the bidentate 2-picolyl azide and/or the resulting
bidentate 5-iodotriazole product act as assisting ligands to exert
acceleratory effect in these reactions.
Experimental procedures, X-ray data of compound 1, Bu4NI3,
and [Cu(CH3CN)4]ClO4 (CIF), and additional figures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(25) While this manuscript was in preparation, CuCl2 was reported
to mediate the radioactive [125I]-triazole formation, presumably via in
situ oxidation of [125I]-NaI by CuCl2, in the preparation of an optical/
nuclear dual-labeling reagent: Yan, R.; El-Emir, E.; Rajkumar, V.;
Robson, M.; Jathoul, A. P.; Pedley, R. B.; Årstad, E. Angew. Chem., Int.
Ed. 2011, 50, 6793−6795.
(26) Kauffman, G. B.; Pinnell, R. P. Inorg. Synth. 1960, 6, 3−6.
(27) Evans’ pKa table: http://evans.harvard.edu/pdf/evans_pka_
table.pdf.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lzhu@chem.fsu.edu.
Notes
The authors declare no competing financial interest.
(28) Wu et al. also observed an enhanced formation of 5-
prototriazole when the amount of TEA increases(ref 8).
(29) DMAP was shown to facilitate 5-iodotriazole formation by
Dzyuba et al.: Smith, N. W.; Polenz, B. P.; Johnson, S. B.; Dzyuba, S.
V. Tetrahedron Lett. 2010, 51, 550−553.
ACKNOWLEDGMENTS
■
This work was supported by the US National Science Founda-
tion (CHE-0809201). We thank Professor Harry Heaney at
Loughborough University (UK) for the critical reading of an
early draft of the manuscript. We thank the Zhu Group members,
in particular Dr. Sreenath Kesavapillai and Mr. David Barsoum, for
assistance during the revision stage.
(30) Buckley, B. R.; Dann, S. E.; Heaney, H. Chem.Eur. J. 2010, 16,
6278−6284.
(31) Diaz-Torres, R.; Alvarez, S. Dalton Trans. 2011, 40, 10742−
10750.
(32) Tsarevsky, N. V.; Braunecker, W. A.; Matyjaszewski, K. J.
Organomet. Chem. 2007, 692, 3212−3222.
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